Inflammatory and Prothrombotic Markers and the Progression of Renal Disease in Elderly Individuals LINDA FRIED,* CAM SOLOMON, † MICHAEL SHLIPAK, ‡ STEPHEN SELIGER, § CATHERINE STEHMAN-BREEN, § ANTHONY J. BLEYER, ¶ PAOLO CHAVES, # CURT FURBERG,** LEWIS KULLER, †† and ANNE NEWMAN ††‡‡ *Renal Section, VA Pittsburgh Healthcare System, and Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; † Department of Biostatistics, University of Washington, Seattle, Washington; ‡ Medicine Service, Veterans Affairs Medical Center, and Departments of Medicine and Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California; § Division of Nephrology, University of Washington, Seattle, Washington;  Renal Section, VA Puget Sound Health Care System, Seattle, Washington; ¶ Section of Nephrology, Wake Forest University School of Medicine, Winston-Salem, North Carolina; # Departments of Medicine and Epidemiology, Johns Hopkins University, Baltimore, Maryland; **Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina; †† Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania; and ‡‡ Division of Geriatric Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Abstract. Inflammatory and prothrombotic markers are ele- vated in individuals with mild to moderate renal disease. It was hypothesized that these markers may also be determinants of the progression of renal disease. The association of six mark- ers—serum C-reactive protein (CRP), white blood cell (WBC) count, fibrinogen, factor VII, albumin, and hemoglobin—with subsequent elevations of creatinine and decline in estimated GFR in the Cardiovascular Health Study, a community-based cohort of elderly individuals, was analyzed. Linear regression was used to determine predictors of an annualized change in serum creatinine as the main outcome. Duration of follow-up was 7 yr for the original cohort and 4 yr for the more recently recruited black cohort. A total of 588 (12.7%) individuals had a decline in estimated GFR of at least 3 ml/min per yr per 1.73 m 2 . Higher CRP (P  0.001), WBC count (P  0.001), fibrinogen (P  0.001), and factor VII (P  0.001) levels and lower albumin (P  0.001) and hemoglobin levels (P  0.001) were associated with a rise in creatinine, after adjusting for age. With additional adjustments for race, gender, baseline creati- nine, systolic and diastolic BP, lipid levels, weight, and pack- years smoking, higher CRP, factor VII, fibrinogen, WBC count, and lower albumin and hemoglobin levels remained associated with a rise in creatinine. Similar results were found for decline in estimated GFR. The decline in GFR was greater with increasing number of inflammatory or prothrombotic markers that were above the median (below for hemoglobin and albumin). Inflammatory and prothrombotic markers are predictors for a change in kidney function in elderly individ- uals. Interventions that reduce inflammation might confer sig- nificant cardiovascular and renal benefits. Patients with renal failure have a high prevalence of cardio- vascular disease, and it has been proposed that atherosclerosis may promote the progression of renal disease in older individ- uals (1). Diamond et al. (2) proposed that mechanisms that result in atherosclerosis also cause glomerulosclerosis and that renal disease in atherosclerosis is not simply the result of ischemia from renal artery disease. In his model, glomerulo- sclerosis results from the influx and accumulation of inflam- matory cells (monocytes and macrophages), with mesangial cells responding in a similar manner to vascular smooth muscle cells. If this hypothesis is correct, then renal disease and cardiovascular disease should share similar risk factors. In particular, inflammatory and prothrombotic factors, which are risk factors for atherosclerosis (3), might be important factors in the progression of renal disease. The relationship of inflam- mation to a subsequent loss of renal function has not been previously examined in a population-based sample. We have previously found that inflammatory and prothrom- botic markers are elevated in elderly individuals with mild to moderate renal insufficiency, a relationship that persisted after adjusting for the greater extent of atherosclerosis that is present in individuals with renal insufficiency (4). In a previous anal- ysis of the Cardiovascular Health Study (CHS), Bleyer et al. (5) found that progression of renal disease after 4 yr was predicted by a low baseline serum albumin, which may be a marker of systemic inflammation. In the current analysis, we examine the relationship of inflammatory and prothrombotic Received December 7, 2003. Accepted September 12, 2004. Correspondence to Dr. Linda Fried, VA Pittsburgh Healthcare System, Uni- versity Drive C, Mailstop 111F-U, Pittsburgh, PA 15240. Phone: 412-688- 6000 x815930; Fax: 412-688-6908; E-mail: Linda.Fried@med.va.gov 1046-6673/1512-3184 Journal of the American Society of Nephrology Copyright © 2004 by the American Society of Nephrology DOI: 10.1097/01.ASN.0000146422.45434.35 J Am Soc Nephrol 15: 3184–3191, 2004