Received June 18, 2008
Accepted on September 8, 2008

ORIGINAL ARTICLES

Serum Concentrations of Markers of TNF and Fas-Mediated Pathways and Renal Function in Nonproteinuric Patients with Type 1 Diabetes

Monika A. Niewczas ^*, Linda H. Ficociello ^*, Amanda C Johnson ^*, William Walker ^*, Elizabeth T. Rosolowsky ^*, Bijan Roshan ^*, James H. Warram ^*, and Andrzej S. Krolewski ^*1

*Research Division of Joslin Diabetes Center, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston Massachusetts; Department of Immunology, Transplant Medicine and Internal Diseases, Warsaw Medical University, Warsaw, Poland; and Division of Endocrinology, Children’s Hospital, Boston, Massachusetts

¹ To whom correspondence should be addressed. E-mail: andrzej.krolewski{at}joslin.harvard.edu.

	Abstract

Background and objectives: The aim of our study was to examine serum markers of the TNF and Fas pathways for association with cystatin-C based estimated glomerular filtration rate (cC-GFR) in subjects with type 1 diabetes (T1DM) and no proteinuria.

Design, setting, participants, & measurements: The study group (the 2nd Joslin Kidney Study) comprised patients with T1DM and normoalbuminuria (NA) (n = 363) or microalbuminuria (MA) (n = 304). Impaired renal function (cC-GFR <90 ml/min) was present in only 10% of patients with NA and 36% of those with MA. We measured markers of the tumor necrosis factor (TNF) pathway [TNF, soluble TNF receptor 1 (sTNFR1), and 2 (sTNFR2)], its downstream effectors [soluble intercellular and soluble vascular adhesion molecules (sICAM-1 and sVCAM-1), interleukin 8 (IL8/CXCL8), monocytes chemoattractant protein-1 (MCP1), and IFN inducible protein-10 (IP10/CXCL10)], the Fas pathway [soluble Fas (sFas) and Fas ligand (sFasL)], CRP, and IL6.

Results: Of these, TNF, sTNFRs, sFas, sICAM-1, and sIP10 were associated with cC-GFR. However, only the TNF receptors and sFas were associated with cC-GFR in multivariate analysis. Variation in the concentration of the TNF receptors had a much stronger impact on GFR than clinical covariates such as age and albumin excretion.

Conclusions: Elevated concentrations of serum markers of the TNF and Fas-pathways are strongly associated with decreased renal function in nonproteinuric type 1 diabetic patients. These effects are independent of those of urinary albumin excretion. Follow-up studies are needed to characterize the role of these markers in early progressive renal function decline.