Genomic biomarkers for chronic kidney disease.
ABSTRACT Chronic kidney disease (CKD) remains a major challenge in nephrology and for public health care, affecting 14% to 15% of the adult US population and consuming significant health care resources. In the next 20 years, the number of patients with end stage renal disease is projected to increase by 50%. Ideal biomarkers that allow early identification of CKD patients at high risk of progression are urgently needed for early and targeted treatment to improve patient care. Recent success of integrating molecular approaches for personalized management of neoplastic diseases, including diagnosis, staging, prognosis, treatment selection, and monitoring, has strongly encouraged kidney researchers to pursue molecular definitions of patients with kidney disease. Challenges for molecular marker identification in CKD are a high degree of cellular heterogeneity of the kidney and the paucity of human tissue availability for molecular studies. Despite these limitations, potential molecular biomarker candidates have been uncovered at multiple levels along the genome--phenome continuum. Here we will review the identification and validation of potential genomic biomarker candidates of CKD and CKD progression in clinical studies. The challenges in predicting CKD progression, as well as the promises and opportunities resulting from a molecular definition of CKD will be discussed.
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ABSTRACT: Noninvasive, cost-effective biomarkers that allow accurate monitoring of graft function are needed in kidney transplantation. Since microRNAs (miRNAs) have emerged as promising disease biomarkers, we sought to establish an miRNA signature in urinary cell pellets comparing kidney transplant patients diagnosed with chronic allograft dysfunction (CAD) with interstitial fibrosis and tubular atrophy and those recipients with normal graft function. Overall, we evaluated 191 samples from 125 deceased donor primary kidney transplant recipients in the discovery, initial validation, and the longitudinal validation studies for noninvasive monitoring of graft function. Of 1733 mature miRNAs studied using microarrays, 22 were found to be differentially expressed between groups. Ontology and pathway analyses showed inflammation as the principal biological function associated with these miRNAs. Twelve selected miRNAs were longitudinally evaluated in urine samples of an independent set of 66 patients, at two time points after kidney transplant. A subset of these miRNAs was found to be differentially expressed between groups early after kidney transplant before histological allograft injury was evident. Thus, a panel of urine miRNAs was identified as potential biomarkers for monitoring graft function and anticipating progression to CAD in kidney transplant patients.Kidney International 09/2013; · 8.52 Impact Factor
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ABSTRACT: Although kidney transplantation has been an important means for the treatment of patients with end stage of renal disease, the long-term survival rate of the renal allograft remains a challenge. The cause of late renal allograft loss, once known as chronic allograft nephropathy, has been renamed "interstitial fibrosis and tubular atrophy" (IF/TA) to reflect the histologic pattern seen on biopsy. The mechanisms leading to IF/TA in the transplanted kidney include inflammation, activation of renal fibroblasts, and deposition of extracellular matrix proteins. Identifying the mediators and factors that trigger IF/TA may be useful in early diagnosis and development of novel therapeutic strategies for improving long-term renal allograft survival and patient outcomes. In this review, we highlight the recent advances in our understanding of IF/TA from three aspects: pathogenesis, diagnosis, and treatment.Fibrogenesis & Tissue Repair 01/2014; 7:15.
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ABSTRACT: Since first sequencing the human genome in 2003, emerging genetic/genomic technologies have ushered in a revolutionary era of medicine that purports to bridge molecular biology and clinical care. The field of translational medicine is charged with mediating this revolution. Sequencing innovations are far outpacing guidelines intended to ease their practice-based applications, including in primary care. As a result, genomic medicine¿s full integration in primary care settings especially, has been slow to materialize. Researchers and clinicians alike face substantial challenges in navigating contentious ethical issues raised in translation and implementation, namely preserving the spirit of whole-person approaches to care; maintaining respect for persons and communities; and translating genetic risk into clinical actionability. This commentary therefore explores practical barriers to, and ethical implications of, incorporating genomic technologies in the primary care sector. These ethical challenges are both philosophical and infrastructural. From a primary care perspective, the commentary further reviews the ethical, legal and social implications of the Center for Disease Control¿s proposed model for assessing the validity and utility of genomic testing and family health history applications. Lastly, the authors provide recommendations for future translational initiatives that aim to maximize the capacities of genomic medicine, without compromising primary care philosophies and foundations of practice.Journal of translational medicine. 08/2014; 12(1):238.