Predictive impact of elevated serum level of IL-18 for early renal dysfunction in type 2 diabetes: an observational follow-up study

Abstract

Aims/hypothesis The early identification of type 2 diabetic patients at risk of developing microalbuminuria-an independent risk factor for renal and cardiovascular diseasesis important to improve the patients' outcomes. We investigated whether serum levels of IL-18, a proinflammatory cytokine, were a predictor of early renal dysfunction. Materials and methods A total of 249 Japanese type 2 diabetic patients without overt proteinuria were enrolled in an observational follow-up study (median follow-up 7 years), and their stage of diabetic nephropathy was classified and their estimated glomerular filtration rate (eGFR) was calculated annually. Results At baseline, serum levels of IL-18 were higher in subjects with microalbuminuria (n=76) than in those with normoalbuminuria (n=173). Elevated serum levels of IL-18 were associated with the progression of nephropathy to a higher stage in normoalbuminuric subjects (118 [ ng/l, p=0.50). The adjusted risk for developing microalbuminuria was 3.6 (95% CI 1.2-10.4) in normoalbuminuric subjects with serum IL-18 levels above the median (≥134.6 ng/l), and was significantly enhanced in those urinary AERs at the upper end of the normal range (7.5 μg/min ≤ AER < 20 μg/min). Furthermore, the annual rate of decline in eGFR, when examined in the study population as a whole, was significantly greater in subjects with serum IL-18 levels above the median than in other subjects. Conclusions/interpretationThe results of our observational follow-up study indicate that elevated serum levels of IL-18 may be a predictor of future renal dysfunction in type 2 diabetic patients with normoalbuminuria.

Diabetic Nephropathy: New Risk Factors and Improvements in Diagnosis

“…Elevated urinary levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a marker of oxidative stress, predict the progression of diabetic nephropathy in patients with T2D [47]. Patients with T1D or T2D and with higher levels of proinflammatory cytokines and chemokines (interleukin 6, interleukin 18, and monocyte chemoattractant protein-1), high-sensitivity Creactive protein (hsCRP, a marker of subclinical inflammation), or adhesion molecules (soluble vascular cellular adhesion molecule-1 and soluble Eselectin) are at higher risk for developing nephropathy and for advancing to more severe kidney disease [48][49][50][51]. In patients with T1D or T2D, elevated levels of tumor necrosis factor-α receptors are also independently associated with increased incidence of impaired kidney function [52,53].…”

Pathophysiological role and therapeutic implications of inflammation in diabetic nephropathy

“…Later studies confirmed the independent and significant association between albuminuria and both serum and urinary IL-18 concentration and, moreover, these levels correlated positively with changes in urinary albumin excretion [118] . Finally, high levels of IL-18 have been suggested as a significant predictor of early renal dysfunction in type 2 diabetes [119] .…”

Role of the TNF pathway in the progression of diabetic nephropathy in KK-Aymice

“…Recently, chronic subclinical inflammation has been thought to be involved in the pathogenesis of DN (4,39). In particular, TNF-␣ is cytotoxic to renal cells and able to induce direct renal injury (8).…”