Chronic kidney disease affects approximately 26 to 30 million adults in the United States and is associated with substantial morbidity and mortality. The underlying causes of CKD and risk for progression in an individual patient are frequently not known in clinical practice. Nevertheless, several pathological processes appear to be common across progressive kidney diseases of diverse etiologies, including progressive tubulointerstitial fibrosis, tubular atrophy, glomerulosclerosis, capillary rarefaction, and vascular sclerosis. Novel non-invasive biomarkers of CKD pathology may provide clarification of the underlying pathobiological processes responsible for CKD in an individual, enabling earlier diagnosis and more accurate prognosis. This proposal is an ancillary study to the CKD Biomarker Consortium (U01DK085660), a group of investigators with wide-ranging biomarker expertise who have access to samples from a number of cohorts of individuals with CKD. The proposal describes a prospective cohort study involving biological sample collection from patients undergoing native kidney biopsy, the gold standard determination for identifying the cause(s) of CKD. We will enroll participants from two hospitals in Boston, Massachusetts and measure urinary and tissue levels of novel biomarkers, including KIM-1, NAG, NGAL, MCP-1, L-FABP, IL-18, HGF, VEGF, IP-10, and CTGF.
In Specific Aim 1, we will correlate urinary biomarker measurements with 13 histologic scores that capture inflammatory, fibrotic, and ischemic pathological processes in the mesangium, tubules, glomeruli, interstitium, and arterioles; further immunohistochemistry will be performed on the most promising biomarkers to identify their tissue distribution and correlation with urinary levels.
In Specific Aim 2, we will test the prospective associations of urinary and tissue biomarkers with renal function decline, defined as a doubling of serum creatinine or the need for renal replacement therapy. We anticipate enrollment of over 900 participants with median follow-up of approximately 5 years. This ancillary proposal will be collaborative and integrated with U01 Consortium investigators and will facilitate multidirectional translation of findings across animal studies, large cohort studies, and the biopsy cohort. Urine, plasma, and DNA samples will be shared with the Consortium for future studies.
Chronic kidney disease is a major public health threat for which the current methods of diagnosis and assessing prognosis are inadequate. The development of new biomarkers of chronic kidney will be facilitated by studies such as the one proposed here, where we will compare urinary and tissue levels of novel biomarkers with actual pathological findings from individuals who have undergone kidney biopsy, which is the 'gold standard' diagnostic tool. Better biomarkers are expected to translate into improved care for the growing number of individuals with chronic kidney disease.
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