Abstract
Despite considerable advancements in medicine, the optimal treatment for chronic kidney disease (CKD), especially diabetic kidney disease (DKD), remains a major challenge. More patients with DKD succumb to death due to cardiovascular events than due to progression to end-stage renal disease (ESRD). Moreover, patients with DKD and ESRD have remarkably poor prognosis. Current studies have appreciated the contribution of inflammation and inflammatory mediators, such as tumor necrosis factor (TNF)-related biomarkers, on the development/progression of DKD. The present review focuses on molecular roles, serum concentrations of TNF receptors (TNFRs), and their association with increased albuminuria, eGFR decline, and all-cause mortality in diabetes. Experimental studies have suggested that DKD progression occurs through the TNFα–TNFR2 inflammatory pathway. Moreover, serum TNFR levels were positively associated with albuminuria and negatively associated with estimated glomerular filtration rate (eGFR), while circulating levels of TNFRs exhibited an independent effect on all-cause mortality and eGFR decline, including ESRD, even after adjusting for existing risk factors. However, their precise function has yet to be elucidated and requires further studies.
Highlights
A total of 850 million individuals suffer from kidney disease worldwide, with one in 10 adults possibly being at risk
ETN treatment decreased serum sTNFR2 levels but not serum sTNFR1 levels. These results suggested that the tumor necrosis factor (TNF)–TNFR2 pathway, but not sTNFR1, may function during kidney injury in this mouse model [60]
Infliximab ameliorated urinary albumin and TNFα excretion Etanercept improved albuminuria and decreased serum sTNFR2 levels TNFR1 or TNFR2 deficiency resulted in significantly less nuclear factor-κB (NF-κB) activation compared with the wild type, with TNFR1 being less than TNFR2 knockout PEG-sTNFR1 significantly reduced tubulointerstitial fibrosis and a progressive renal function decline TNFR1 or TNFR2 deficiency protects mice from cisplatin-induced AKI
Summary
A total of 850 million individuals suffer from kidney disease worldwide, with one in 10 adults possibly being at risk. Diabetic kidney disease (DKD) has been one of the most significant diseases given its relationship with both progression to ESRD and morbidity and mortality from cardiovascular diseases [1]. To prevent ESRD, identifying patients at high risk for progression of DKD at an early stage and providing intensive treatment are imperative. Increased expression of cell adhesion molecules, chemokines, and inflammatory cytokines have been observed in the kidneys of patients with diabetes. STNFR1 and sTNFR2 are not deviating enzymes appearing after cytolysis but rather appear in the blood at the initial stage of inflammation. The present review describes the role of chronic inflammation in the pathogenesis of DKD, focuses on the relationship between TNF–TNFR signaling and DKD progression, and highlights the utility of TNFRs as a biomarker
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