Activation of the CD40 receptor on the proximal tubular epithelium of the kidney results in fibrosis and inflammation in experimental models of kidney injury. Soluble CD40 ligand is released by activated platelets. The role of CD40-soluble CD40 ligand in patients with ischemic renal disease is unknown. Plasma levels of CD40 and soluble CD40 ligand were measured by enzyme-linked immunosorbent assay in a single center cohort of 60 patients with renal artery stenosis recruited from Salford Royal Hospital, Manchester, United Kingdom. A natural log transformation of CD40 and soluble CD40 ligand was performed to normalize the data. Estimated glomerular filtration rate was used as the primary indicator of renal function. By univariate analysis, low baseline levels of circulating CD40 (R(2)=0.06; P<0.05) and baseline creatinine (R(2)=0.08; P=0.022) were associated with loss of kidney function at 1-year follow-up, whereas soluble CD40 ligand was not (R(2)=0.02; P=ns). In a multiple linear regression model, CD40 (P<0.02) and baseline creatinine (P<0.01) continued to be significantly associated with a decline in renal function (model R(2)=0.17; P<0.005). Baseline CD40 levels were somewhat lower in patients who died during follow-up (survivors, 7.3±0.9 pg/mL, n=48 versus nonsurvivors, 6.7±1.0 pg/mL, n=12; P=0.06). The CD40/soluble CD40 ligand signaling cascade may be a novel mechanism contributing to the development and progression of renal injury in patients with atherosclerotic renal artery stenosis.