Inflammation and Trajectory of Renal Function in Community-Dwelling Older Adults

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Abstract

<div class="section"> <a class="named-anchor" id="S1">  </a> <h5 class="section-title" id="d5291099e188">BACKGROUND/OBJECTIVES</h5> <p id="P3">Limited evidence suggests that the inflammatory state of aging is a risk factor for accelerated renal function (RF) decline. We examined this hypothesis using inflammatory biomarkers and RF collected over a 9-year follow-up in relatively healthy individuals enrolled in the InCHIANTI study. </p> </div><div class="section"> <a class="named-anchor" id="S2">  </a> <h5 class="section-title" id="d5291099e193">DESIGN</h5> <p id="P4">Longitudinal</p> </div><div class="section"> <a class="named-anchor" id="S3">  </a> <h5 class="section-title" id="d5291099e198">SETTING</h5> <p id="P5">Community</p> </div><div class="section"> <a class="named-anchor" id="S4">  </a> <h5 class="section-title" id="d5291099e203">PARTICIPANTS</h5> <p id="P6">Participants included 687 adults age 60 and older with baseline estimated glomerular filtration rate (eGFR)≥60 ml/min/1.73m <sup>2</sup> and no diabetes mellitus (DM). </p> </div><div class="section"> <a class="named-anchor" id="S5">  </a> <h5 class="section-title" id="d5291099e211">MEASURES</h5> <p id="P7">eGFR, proxy for RF, was determined using the CKD-EPI equation at baseline and then at 3-, 6-, and 9-year follow-ups. Incident chronic kidney disease (CKD) was defined as new-onset eGFR<60 ml/min/1.73m <sup>2</sup> at each follow-up. Predictors included baseline and time-dependent inflammatory biomarkers: soluble tumor necrosis factor alpha receptors (sTNFα-R1 and -R2), interleukin(IL)-6, IL-18, IL-1β, IL-1 receptor antagonist, and high sensitivity C-reactive protein. </p> </div><div class="section"> <a class="named-anchor" id="S6">  </a> <h5 class="section-title" id="d5291099e219">Results</h5> <p id="P8">Higher baseline sTNFα-R1 was significantly associated with lower eGFR over 9 years, independent of DM or blood pressure:(Baseline:β̂=−0.39, <i>p</i> = 0.001; 3-year: β̂=−0.26, <i>p</i>=0.001; 6-year: β̂=−0.36, <i>p</i>=0.001; 9-year: β̂=−0.47, <i>p</i>=0.001). The rate of TNFα-R1 change was significantly associated with rate of eGFR change (β̂=−0.18, <i>p</i>=0.001). Baseline sTNFα-R1 predicted incident CKD [per 1-SD increment]: 3-year: relative risk (RR)=1.3 (95% CI: 1.1–1.5); 6-year: RR=1.5 (1.1–2.2); 9-year RR=1.6 (1.1–2.2,). Similar results were found for sTNFα-R2. </p> </div><div class="section"> <a class="named-anchor" id="S7">  </a> <h5 class="section-title" id="d5291099e239">Conclusion</h5> <p id="P9">Baseline and the rate of change in TNFα receptors were significantly associated with faster RF decline and incident CKD among older adults independent of DM or blood pressure. </p> </div>

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TNF was originally described as a circulating factor that can cause necrosis of tumours, but has since been identified as a key regulator of the inflammatory response. This review describes the known signalling pathways and cell biological effects of TNF, and our understanding of the role of TNF in human disease. TNF interacts with two different receptors, designated TNFR1 and TNFR2, which are differentially expressed on cells and tissues and initiate both distinct and overlapping signal transduction pathways. These diverse signalling cascades lead to a range of cellular responses, which include cell death, survival, differentiation, proliferation and migration. Vascular endothelial cells respond to TNF by undergoing a number of pro-inflammatory changes, which increase leukocyte adhesion, transendothelial migration and vascular leak and promote thrombosis. The central role of TNF in inflammation has been demonstrated by the ability of agents that block the action of TNF to treat a range of inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease and psoriasis. The increased incidence of infection in patients receiving anti-TNF treatment has highlighted the physiological role of TNF in infectious diseases. 2007 Pathological Society of Great Britain and Ireland

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Juan F. Navarro-González, Carmen Mora-Fernández, Mercedes Muros de Fuentes … (2011)

Many lines of evidence, ranging from in vitro experiments and pathological examinations to epidemiological studies, show that inflammation is a cardinal pathogenetic mechanism in diabetic nephropathy. Thus, modulation of inflammatory processes in the setting of diabetes mellitus is a matter of great interest for researchers today. The relationships between inflammation and the development and progression of diabetic nephropathy involve complex molecular networks and processes. This Review, therefore, focuses on key proinflammatory molecules and pathways implicated in the development and progression of diabetic nephropathy: the chemokines CCL2, CX3CL1 and CCL5 (also known as MCP-1, fractalkine and RANTES, respectively); the adhesion molecules intercellular adhesion molecule 1, vascular cell adhesion protein 1, endothelial cell-selective adhesion molecule, E-selectin and α-actinin 4; the transcription factor nuclear factor κB; and the inflammatory cytokines IL-1, IL-6, IL-18 and tumor necrosis factor. Advances in the understanding of the roles that these inflammatory pathways have in the context of diabetic nephropathy will facilitate the discovery of new therapeutic targets. In the next few years, promising new therapeutic strategies based on anti-inflammatory effects could be successfully translated into clinical treatments for diabetic complications, including diabetic nephropathy.

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Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes.

Monika A Niewczas, Tomohito Gohda, Jan Skupien … (2012)

Levels of proinflammatory cytokines associate with risk for developing type 2 diabetes but whether chronic inflammation contributes to the development of diabetic complications, such as ESRD, is unknown. In the 1990s, we recruited 410 patients with type 2 diabetes for studies of diabetic nephropathy and recorded their characteristics at enrollment. During 12 years of follow-up, 59 patients developed ESRD (17 per 1000 patient-years) and 84 patients died without ESRD (24 per 1000 patient-years). Plasma markers of systemic inflammation, endothelial dysfunction, and the TNF pathway were measured in the study entry samples. Of the examined markers, only TNF receptors 1 and 2 (TNFR1 and TNFR2) associated with risk for ESRD. These two markers were highly correlated, but ESRD associated more strongly with TNFR1. The cumulative incidence of ESRD for patients in the highest TNFR1 quartile was 54% after 12 years but only 3% for the other quartiles (P<0.001). In Cox proportional hazard analyses, TNFR1 predicted risk for ESRD even after adjustment for clinical covariates such as urinary albumin excretion. Plasma concentration of TNFR1 outperformed all tested clinical variables with regard to predicting ESRD. Concentrations of TNFRs moderately associated with death unrelated to ESRD. In conclusion, elevated concentrations of circulating TNFRs in patients with type 2 diabetes at baseline are very strong predictors of the subsequent progression to ESRD in subjects with and without proteinuria.