Urinary Peptidome May Predict Renal Function Decline in... : Journal of the American Society of Nephrology (original) (raw)

CLINICAL RESEARCH

Urinary Peptidome May Predict Renal Function Decline in Type 1 Diabetes and Microalbuminuria

Merchant, Michael L.*,†; Perkins, Bruce A.‡,§; Boratyn, Grzegorz M.*,†; Ficociello, Linda H.‡; Wilkey, Daniel W.*,†; Barati, Michelle T.*,†; Bertram, Clinton C.*,†; Page, Grier P.‖; Rovin, Brad H.¶; Warram, James H.‡; Krolewski, Andrzej S.‡,**; Klein, Jon B.*,†,††

*Kidney Disease Program and

†Clinical Proteomics Center, University of Louisville, and

††Veterans Administration Medical Center, Louisville, Kentucky;

‡Research Division, Joslin Diabetes Center, and

**Department of Medicine, Brigham & Women Hospital, Harvard Medical School, Boston, Massachusetts;

§Division of Endocrinology, University of Toronto, Toronto, Ontario, Canada;

‖Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama; and

¶Department of Medicine, Ohio State University School of Medicine, Columbus, Ohio

Correspondence: Dr. Andrzej S. Krolewski, Joslin Diabetes Center, Room 368, One Joslin Place, Boston, MA 02215. Phone: 617-732-2668; Fax: 617-732-2667; E-mail: [email protected]; or Dr. Jon Klein, Donald Baxter Research Building, Room 110E, 570 S. Preston Street, Louisville, KY 40202. Phone: 502-852-0245; Fax: 502-852-4384; E-mail: [email protected]

Received December 3, 2008

Accepted May 7, 2009

Abstract

One third of patients with type 1 diabetes and microalbuminuria experience an early, progressive decline in renal function that leads to advanced stages of chronic kidney disease and ESRD. We hypothesized that the urinary proteome may distinguish between stable renal function and early renal function decline among patients with type 1 diabetes and microalbuminuria. We followed patients with normal renal function and microalbuminuria for 10 to 12 yr and classified them into case patients (n = 21) with progressive early renal function decline and control subjects (n = 40) with stable renal function. Using liquid chromatography matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, we identified three peptides that decreased in the urine of patients with early renal function decline [fragments of α1(IV) and α1(V) collagens and tenascin-X] and three peptides that increased (fragments of inositol pentakisphosphate 2-kinase, zona occludens 3, and FAT tumor suppressor 2). In renal biopsies from patients with early nephropathy from type 1 diabetes, we observed increased expression of inositol pentakisphosphate 2-kinase, which was present in granule-like cytoplasmic structures, and zona occludens 3. These results indicate that urinary peptide fragments reflect changes in expression of intact protein in the kidney, suggesting new potential mediators of diabetic nephropathy and candidate biomarkers for progressive renal function decline.