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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK093574-01A1
Application #
8372163
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (M3))
Program Officer
Kimmel, Paul
Project Start
2012-09-01
Project End
2016-06-30
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$680,431
Indirect Cost
$283,435
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Srivastava, Anand; Kaze, Arnaud D; McMullan, Ciaran J et al. (2018) Uric Acid and the Risks of Kidney Failure and Death in Individuals With CKD. Am J Kidney Dis 71:362-370
Srivastava, Anand; Palsson, Ragnar; Kaze, Arnaud D et al. (2018) The Prognostic Value of Histopathologic Lesions in Native Kidney Biopsy Specimens: Results from the Boston Kidney Biopsy Cohort Study. J Am Soc Nephrol 29:2213-2224
Leaf, David E; Siew, Edward D; Eisenga, Michele F et al. (2018) Fibroblast Growth Factor 23 Associates with Death in Critically Ill Patients. Clin J Am Soc Nephrol 13:531-541
Waikar, Sushrut S; McMahon, Gearoid M (2018) Expanding the Role for Kidney Biopsies in Acute Kidney Injury. Semin Nephrol 38:12-20
Mendu, Mallika L; Ciociolo Jr, George R; McLaughlin, Sarah R et al. (2017) A Decision-Making Algorithm for Initiation and Discontinuation of RRT in Severe AKI. Clin J Am Soc Nephrol 12:228-236
Leaf, David E; Jacob, Kirolos A; Srivastava, Anand et al. (2017) Fibroblast Growth Factor 23 Levels Associate with AKI and Death in Critical Illness. J Am Soc Nephrol 28:1877-1885
Kota, Satya K; Pernicone, Elizabeth; Leaf, David E et al. (2017) BPI Fold-Containing Family A Member 2/Parotid Secretory Protein Is an Early Biomarker of AKI. J Am Soc Nephrol 28:3473-3478
Cardenas-Gonzalez, Mariana; Srivastava, Anand; Pavkovic, Mira et al. (2017) Identification, Confirmation, and Replication of Novel Urinary MicroRNA Biomarkers in Lupus Nephritis and Diabetic Nephropathy. Clin Chem 63:1515-1526
Leaf, David E; Waikar, Sushrut S (2017) End Points for Clinical Trials in Acute Kidney Injury. Am J Kidney Dis 69:108-116
Birmingham, Daniel J; Merchant, Michael; Waikar, Sushrut S et al. (2017) Biomarkers of lupus nephritis histology and flare: deciphering the relevant amidst the noise. Nephrol Dial Transplant 32:i71-i79

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