ABSTRACT
Chronic kidney diseases (CKD) are a major health problem affecting approximately 10% of the world's population and posing increasing challenges to the healthcare system. While CKD encompasses a broad spectrum of pathological processes and diverse etiologies, the classification of kidney disease is currently based on clinical findings or histopathological categorizations. This descriptive classification is agnostic towards the underlying disease mechanisms and has limited progress towards the ability to predict disease prognosis and treatment responses. To gain better insight into the complex and heterogeneous disease pathophysiology of CKD, a systems biology approach can be transformative. Rather than examining one factor or pathway at a time, as in the reductionist approach, with this strategy a broad spectrum of information is integrated, including comprehensive multi-omics data, clinical phenotypic information, and clinicopathological parameters. In recent years, rapid advances in mathematical, statistical, computational, and artificial intelligence methods enable the mapping of diverse big data sets. This holistic approach aims to identify the molecular basis of CKD subtypes as well as individual determinants of disease manifestation in a given patient. The emerging mechanism-based patient stratification and disease classification will lead to improved prognostic and predictive diagnostics and the discovery of novel molecular disease-specific therapies.
Subject(s)
Nephrology/methods , Renal Insufficiency, Chronic/pathology , Animals , Humans , PrognosisABSTRACT
PURPOSE OF REVIEW: Current clinical pathological classifications of glomerular diseases are inadequate at predicting patient disease progression or response to therapy. With the advent of precision medicine and its successes in oncology, it is important to understand if similar approaches in glomerular diseases can improve patient management. The purpose of this review is to summarize approaches to obtain comprehensive molecular profiles from human biopsies and utilize them to define the pathophysiology of glomerular failure. RECENT FINDINGS: Multicenter research networks have provided the framework to capture both prospective clinical disease course and patterns of end organ damage in biopsy cohorts. With these sample and data sets in hand, efforts are progressing towards molecular disease characterization, identification of novel prognostic marker, development of more precise clinical trials and discovery of predictive biomarkers to more effectively stratify patients to appropriate treatment regiments. Partnerships between academia, public funding agencies and private companies seek to improve timelines and maximize resources while also leveraging domain expertise in an integrated framework to holistically understand disease. SUMMARY: The application of system biology techniques within team science frameworks across disciplines and continents will seek to realize the impact of precision medicine to bring urgently needed novel therapeutic options to patients with glomerular disease.
Subject(s)
Kidney Glomerulus/physiopathology , Renal Insufficiency/therapy , Systems Biology/methods , Humans , Multicenter Studies as Topic , Precision Medicine , Renal Insufficiency/diagnosis , Renal Insufficiency/physiopathologyABSTRACT
The global nephrology community recognises the need for a cohesive plan to address the problem of chronic kidney disease (CKD). In July, 2016, the International Society of Nephrology hosted a CKD summit of more than 85 people with diverse expertise and professional backgrounds from around the globe. The purpose was to identify and prioritise key activities for the next 5-10 years in the domains of clinical care, research, and advocacy and to create an action plan and performance framework based on ten themes: strengthen CKD surveillance; tackle major risk factors for CKD; reduce acute kidney injury-a special risk factor for CKD; enhance understanding of the genetic causes of CKD; establish better diagnostic methods in CKD; improve understanding of the natural course of CKD; assess and implement established treatment options in patients with CKD; improve management of symptoms and complications of CKD; develop novel therapeutic interventions to slow CKD progression and reduce CKD complications; and increase the quantity and quality of clinical trials in CKD. Each group produced a prioritised list of goals, activities, and a set of key deliverable objectives for each of the themes. The intended users of this action plan are clinicians, patients, scientists, industry partners, governments, and advocacy organisations. Implementation of this integrated comprehensive plan will benefit people who are at risk for or affected by CKD worldwide.
Subject(s)
Disease Management , Global Health , Health Priorities , Renal Insufficiency, Chronic/therapy , Acute Kidney Injury/prevention & control , Clinical Trials as Topic , Congresses as Topic , Disease Progression , Drug Discovery , Drug Evaluation, Preclinical , Genetic Predisposition to Disease , Humans , Practice Guidelines as Topic , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/epidemiology , Renal Insufficiency, Chronic/etiology , Risk FactorsABSTRACT
IgA nephropathy (IgAN) is a clinically and pathologically heterogeneous disease. Endocapillary proliferation is associated with higher risk of progressive disease, and clinical studies suggest that corticosteroids mitigate this risk. However, corticosteroids are associated with protean cellular effects and significant toxicity. Furthermore the precise mechanism by which they modulate kidney injury in IgAN is not well delineated. To better understand molecular pathways involved in the development of endocapillary proliferation and to identify novel specific therapeutic targets, we evaluated the glomerular transcriptome of microdissected kidney biopsies from 22 patients with IgAN. Endocapillary proliferation was defined according to the Oxford scoring system independently by 3 nephropathologists. We analyzed mRNA expression using microarrays and identified transcripts differentially expressed in patients with endocapillary proliferation compared to IgAN without endocapillary lesions. Next, we employed both transcription factor analysis and in silico drug screening and confirmed that the endocapillary proliferation transcriptome is significantly enriched with pathways that can be impacted by corticosteroids. With this approach we also identified novel therapeutic targets and bioactive small molecules that may be considered for therapeutic trials for the treatment of IgAN, including resveratrol and hydroquinine. In summary, we have defined the distinct molecular profile of a pathologic phenotype associated with progressive renal insufficiency in IgAN. Exploration of the pathways associated with endocapillary proliferation confirms a molecular basis for the clinical effectiveness of corticosteroids in this subgroup of IgAN, and elucidates new therapeutic strategies for IgAN.
Subject(s)
Glomerulonephritis, IGA/metabolism , Transcriptome , Adrenal Cortex Hormones/therapeutic use , Adult , Computer Simulation , Drug Evaluation, Preclinical , Female , Glomerulonephritis, IGA/drug therapy , Glomerulonephritis, IGA/pathology , Humans , Kidney Glomerulus/blood supply , Kidney Glomerulus/pathology , Male , Middle Aged , Molecular Targeted Therapy , Neovascularization, Pathologic/metabolism , Phenotype , Young AdultABSTRACT
The National Center for Integrative and Biomedical Informatics (NCIBI) is one of the eight NCBCs. NCIBI supports information access and data analysis for biomedical researchers, enabling them to build computational and knowledge models of biological systems to address the Driving Biological Problems (DBPs). The NCIBI DBPs have included prostate cancer progression, organ-specific complications of type 1 and 2 diabetes, bipolar disorder, and metabolic analysis of obesity syndrome. Collaborating with these and other partners, NCIBI has developed a series of software tools for exploratory analysis, concept visualization, and literature searches, as well as core database and web services resources. Many of our training and outreach initiatives have been in collaboration with the Research Centers at Minority Institutions (RCMI), integrating NCIBI and RCMI faculty and students, culminating each year in an annual workshop. Our future directions include focusing on the TranSMART data sharing and analysis initiative.
Subject(s)
Biomedical Research , Information Dissemination , Integrative Medicine , Medical Informatics , Databases as Topic , Forecasting , Goals , National Institutes of Health (U.S.) , United StatesABSTRACT
BACKGROUND: Lipoxins are lipoxygenase-derived eicosanoids with anti-inflammatory and proresolution bioactivities in vitro and in vivo. We have previously demonstrated that the stable synthetic LXA4 analog 15-epi-16-(FPhO)-LXA4-Me is renoprotective in murine renal ischemia/reperfusion injury, as gauged by lower serum creatinine, attenuated leukocyte infiltration, and reduced morphologic tubule injury. METHODS: We employed complementary oligonucleotide microarray and bioinformatic analyses to probe the transcriptomic events that underpin lipoxin renoprotection in this setting. RESULTS: Microarray-based analysis identified three broad categories of genes whose mRNA levels are altered in response to ischemia/reperfusion injury, including known genes previously implicated in the pathogenesis of ischemia/reperfusion injury [e.g., intercellular adhesion molecule-1 (ICAM-1), p21, KIM-1], known genes not previously associated with ischemia/reperfusion injury, and cDNAs representing yet uncharacterized genes. Characterization of expressed sequence tags (ESTs) displayed on microarrays represents a major challenge in studies of global gene expression. A bioinformatic annotation pipeline successfully annotated a large proportion of ESTs modulated during ischemia/reperfusion injury. The differential expression of a representative group of these ischemia/reperfusion injury-modulated genes was confirmed by real-time polymerase chain reaction. Prominent among the up-regulated genes were claudin-1, -3, and -7, and ADAM8. Interestingly, the former response was claudin-specific and was not observed with other claudins expressed by the kidney (e.g., claudin-8 and -6) or indeed with other components of the renal tight junctions (e.g., occludin and junctional adhesion molecule). Noteworthy among the down-regulated genes was a cluster of transport proteins (e.g., aquaporin-1) and the zinc metalloendopeptidase meprin-1 beta implicated in renal remodeling. CONCLUSION: Treatment with the lipoxin analog 15-epi-16-(FPhO)-LXA4-Me prior to injury modified the expression of many differentially expressed pathogenic mediators, including cytokines, growth factors, adhesion molecules, and proteases, suggesting a renoprotective action at the core of the pathophysiology of acute renal failure (ARF). Importantly, this lipoxin-modulated transcriptomic response included many genes expressed by renal parenchymal cells and was not merely a reflection of a reduced renal mRNA load resulting from attenuated leukocyte recruitment. The data presented herein suggest a framework for understanding drivers of kidney injury in ischemia/reperfusion and the molecular basis for renoprotection by lipoxins in this setting.