Structural damage in diabetic nephropathy is associated with TNF-α system activity

Abstract

In experimental animal studies, tumour necrosis factor-α (TNF-α) contributed to renal hypertrophy during diabetes, and antibodies against TNF-α have led to improved histological lesions in animals with nephrotoxicity and diabetic nephropathy. We aimed to evaluate TNF-α system activity in association with renal histology in patients with type 2 diabetes. This is a prospective, cross-sectional study of 22 patients with type 2 diabetes (16 men), 13 with microalbuminuria and 9 with normoalbuminuria. Plasma-soluble TNF-α receptor 1 and 2 (sTNFR1 and sTNFR2) concentrations were used as surrogates of TNF-α system activity. Glomerular filtration rate (GFR) was analysed using I(125)-Iodothalamine. Albumin excretion rate (AER) and a renal biopsy were performed in all subjects. AER did not associate significantly with mesangial expansion or interstitial fraction in these subjects (r < 0.12, P > 0.5). AER was also not associated with either sTNFR1 or sTNFR2 levels. However, after controlling for GFR, the correlation between AER and sTNFR1 became significant (r = 0.47, P = 0.03). sTNFR1 correlated with age (r = 0.65, P < 0.001), mesangial expansion (r = 0.59, P = 0.004) and interstitial fraction (r = 0.58, P = 0.005). After controlling for age, body mass index and blood pressure, the association of TNFR1 with mesangial expansion persisted significant. Circulating sTNFR2 concentrations were not significantly associated with histological changes. In summary, structural kidney damage in patients with type 2 diabetes is associated with TNF-α system activity and specifically with plasma sTNFR1 concentrations.

Longitudinal Changes in Measured Glomerular Filtration Rate, Renal Fibrosis and Biomarkers in a Rat Model of Type 2 Diabetic Nephropathy

“…Increased serum levels of both TNFR1 and TNFR2 have been shown to correlate with GFR in diabetic patients and have the potential as predictors of progressive renal disease in diabetes [36]. Structural kidney damage in patients with type 2 diabetes is associated with TNF-α activity and specifically with plasma concentrations of soluble TNFR1 [37]. Our current study further supports the potential pathophysiological role of TNF-α pathway in the development of diabetic kidney damage and dysfunction.…”

Plasma Apolipoprotein L1 Levels Do Not Correlate with CKD

“…[45][46][47][48][49][50] Although the cytokine levels were not associated with APOL1 genotype, several cytokines were independent risk factors for both CKD phenotypes. Although it is unclear how and why inflammatory cytokines are elevated in the setting of CKD, it is possible these cytokines may represent an additional pathogenic trigger that initiates or exacerbates CKD in individuals with APOL1 risk genotypes.…”

Baseline Markers of Inflammation Are Associated With Progression to Macroalbuminuria in Type 1 Diabetic Subjects

“…The same group also performed a study in 410 patients with type 2 diabetes, showing that elevated levels of sTNFRs, particularly TNFR-2, were strong predictors of progression to end-stage renal disease (24). Interestingly, the fact that the association of high levels of sTNFR1 and 2 with early renal function loss in type 1 diabetes is independent of the levels of either free or total circulating TNF levels (25) argues for the direct involvement of sTNFRs through a specific but not-yet-defined pathway leading to deterioration of kidney function and progression to end-stage kidney disease. Fernández-Real et al (25), in studies aimed at evaluating the role of the TNF system activity on structural kidney damage in type 2 diabetes, reported a direct correlation between the levels of sTNFR-1 and mesangial expansion.…”

“…Interestingly, the fact that the association of high levels of sTNFR1 and 2 with early renal function loss in type 1 diabetes is independent of the levels of either free or total circulating TNF levels (25) argues for the direct involvement of sTNFRs through a specific but not-yet-defined pathway leading to deterioration of kidney function and progression to end-stage kidney disease. Fernández-Real et al (25), in studies aimed at evaluating the role of the TNF system activity on structural kidney damage in type 2 diabetes, reported a direct correlation between the levels of sTNFR-1 and mesangial expansion. The above studies together with our own data strongly support the lack of association of general markers of inflammation like CRP and IL-6 and initiation and progression of kidney disease in diabetes.…”