Serum concentrations of markers of TNFalpha and Fas-mediated pathways and renal function in nonproteinuric patients with type 1 diabetes.
OBJECTIVE
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.


METHODS
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 alpha (TNFalpha) pathway [TNFalpha, 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 IFNgamma inducible protein-10 (IP10/CXCL10)], the Fas pathway [soluble Fas (sFas) and Fas ligand (sFasL)], CRP, and IL6.


RESULTS
Of these, TNFalpha, 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 TNFalpha 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.
Niewczas
Monika A
MA
Research Division of Joslin Diabetes Center, Boston, MA 02215, USA.
Ficociello
Linda H
LH
Johnson
Amanda C
AC
Walker
William
W
Rosolowsky
Elizabeth T
ET
Roshan
Bijan
B
Warram
James H
JH
Krolewski
Andrzej S
AS
D000328:Adult; D000419:Albuminuria / Q000276:immunology / Q000503:physiopathology; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis; D018932:Chemokine CCL2 / Q000097:blood; D054357:Chemokine CXCL10 / Q000097:blood; D003430:Cross-Sectional Studies; D055316:Cystatin C / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000276:immunology* / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000276:immunology / Q000503:physiopathology; D053222:Fas Ligand Protein / Q000097:blood; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D007668:Kidney / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood; D019014:fas Receptor / Q000097:blood*
D015415:Biomarkers; C111835:CCL2 protein, human; C525030:CST3 protein, human; C114753:CXCL10 protein, human; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D055316:Cystatin C; C491901:FAS protein, human; D053222:Fas Ligand Protein; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506235:TNFRSF1A protein, human; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D019014:fas Receptor; D018799:Intercellular Adhesion Molecule-1; D002097:C-Reactive Protein