High levels of circulating TNFR1 increase the risk of all‐cause mortality and progression of renal disease in type 2 diabetic nephropathy

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The Spanish PRONEDI trial (PROgresión de NEfropatía DIabética)1 was a prospective study in which the combination of lisinopril and irbesartan was compared to either agent alone at optimal high doses. The primary composite outcome was a >50% increase in baseline serum creatinine level, end‐stage renal disease, or death, and the study showed no benefit of the combination of lisinopril and irbersartan on the risk of progression of type 2 diabetic nephropathy. A prospective clinical trial, like the PRONEDI study, offers an ideal frame to analyze the role of hypothetical pathogenic factors on the progression of the disease.
In the past decade, several major new findings about diabetes mellitus and its complications have changed the way we think about this disease. We now know that diabetes is not only a metabolic disorder and that diverse molecules associated with inflammation and the innate immune system play a significant role in its development.
Several studies have supported the role of proinflammatory cytokines such as TNFα in the pathogenesis of diabetes.2 Monocytes and macrophages are the primary source of TNFα, although intrinsic renal cells are also able to synthesize this cytokine.4 TNFα can promote the development and progression of diabetic microvascular complications, including renal damage, and has been implicated in the haemodynamic misbalance between vasodilators and vasoconstrictive mediators, which results in altered intraglomerular blood flow and glomerular filtration rate (GFR).5 Serum levels of TNFα are 3–4 times higher in patients with type 2 DIABETES than in those without diabetes and are higher in patients with microalbuminuria than in patients with normal albumin levels.7
The function of TNFα is mediated by two structurally distinct receptors, TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). TNFR1 is expressed in the healthy kidney and is increased in inflammatory kidney diseases,8 such as human lupus nephritis.9 By contrast, TNFR2 is not usually expressed in healthy kidney tissue, but it is increased in inflamed tissue.8
Circulating levels of TNFR1 and TNFR2 were recently reported to be robust independent predictors of progression of incipient diabetic nephropathy.11 Otherwise we have no data about its involvement in advanced stages. Renin‐angiotensin‐aldosterone system blockers have proven to be able to prevent and slow the progression of diabetic nephropathy.13 In addition to their haemodynamic properties, these drugs have anti‐inflammatory features. In experimental models, enalapril almost completely abolishes local TNFα and reduces urinary TNFα level.14 To our knowledge this effect has not been explored in humans.
The purpose of this study was to analyze the association between circulating levels of TNFR1 and TNFR2 and progression of type II diabetic nephropathy as a substudy of the Spanish Progression de Nefropatía Diabética (PRONEDI) trial. We also determine whether optimal doses of renin‐angiotensin system (RAS) blockers in monotherapy or in combination (dual blockade) have any effect on circulating levels of TNFR1 and TNFR2.
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