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Soluble Urokinase Plasminogen Activator Receptor Predicts 1112 Diabetes Care Volume 42, June 2019 Viktor Rotbain Curovic,1 Simone Theilade,1 Soluble Urokinase Plasminogen Signe A. Winther,1 Nete Tofte,1 Jesper Eugen-Olsen,2 Frederik Persson,1 Activator Receptor Predicts Tine W. Hansen,1 Jørgen Jeppesen,3,4 and Cardiovascular Events, Kidney Peter Rossing1,4 Function Decline, and Mortality in Patients With Type 1 Diabetes Diabetes Care 2019;42:1112–1119 | https://doi.org/10.2337/dc18-1427 OBJECTIVE Soluble urokinase plasminogen activator receptor (suPAR) is an important in- flammatory biomarker implicated in endothelial and podocyte dysfunction. How- ever, suPAR’s predictive qualities for complications in type 1 diabetes have yet to be determined. We investigated the prognostic value of suPAR for the development of cardiovascularevents,declineinrenalfunction, andmortalityinpatientswith type1 diabetes. RESEARCH DESIGN AND METHODS We included 667 patients with type 1 diabetes with various degrees of albuminuria inaprospective study. End points were cardiovascular events (cardiovascular death, nonfatal acute myocardial infarction, nonfatal stroke, or coronary or peripheral arterial interventions), estimated glomerular filtration rate (eGFR) decline ‡30%, progressionfromlowertohigheralbuminuricstate,developmentofend-stagerenal disease (ESRD), and mortality. Follow-up was 5.2–6.2 years. Results were adjusted for known risk factors. Hazard ratios (HRs) are presented per doubling of suPAR with 95% CI. Relative integrated discrimination improvement (rIDI) was calculated. 1Steno Diabetes Center Copenhagen, Gentofte, Denmark RESULTS 2Clinical ResearchCentre,CopenhagenUniversity Quantification of suPAR was available in all participants; median (interquartile Hospital Hvidovre, Hvidovre, Denmark 3 range) was 3.4 ng/mL (2.7–4.5). The adjusted HR (95% CI) for cardiovascular events Department of Medicine, Amager Hvidovre Hospital, Glostrup, Denmark CARDIOVASCULAR AND METABOLIC RISK n n n n ( = 94), progression in albuminuria ( = 36), eGFR decline ( = 93), ESRD ( = 23), and 4University of Copenhagen, Copenhagen, Den- mortality (n = 58) were 3.13 (1.96–5.45, P < 0.001), 1.27 (0.51–3.19, P = 0.61), 2.93 mark (1.68–5.11, P < 0.001), 2.82 (0.73–11.9, P = 0.13), and 4.13 (1.96–8.69, P < 0.001), Corresponding author: Viktor Rotbain Curovic, respectively. rIDI was significant for cardiovascular events (22.6%, P < 0.001), eGFR [email protected] decline (14.4%, P < 0.001), and mortality (23.9%, P < 0.001). Received 4 July 2018 and accepted 25 February 2019 CONCLUSIONS © 2019 by the American Diabetes Association. In patients with type 1 diabetes and a broad range of albuminuria, a higher level of Readers may use this article as long as the work suPAR is a significant and independent risk factor for cardiovascular events, decline is properly cited, the use is educational and not for profit, and the work is not altered. More infor- in eGFR ‡30%, and mortality. In addition, suPAR contributes significantly to dis- mation is available at http://www.diabetesjournals crimination for the end points. .org/content/license. care.diabetesjournals.org Rotbain Curovic and Associates 1113 Type 1 diabetes is a serious and well- kidney disease (CKD), suggested by its Center Copenhagen. The details of the known risk factor for development of activation of podocytes in pathological study have previously been described cardiovascular disease (1,2) and diabetic conditions (22). Podocytes have addition- (29). In short, participants had type 1 kidney disease (DKD) (3) and a strong risk ally been theorized to be a main mechanism diabetes according to World Health Or- factor for mortality (4). Furthermore, as and influence in the development of DKD ganization criteria and were $18 years of type 1 diabetes often is diagnosed at a specifically (23), possibly driven by, or age. The cohort was stratified by levels of young age (5), patients are at high risk of associated with, high suPAR levels (24). albuminuria (normo-, micro-, and macro- developing complications early, mark- As such it is suggested that suPAR has a albuminuria). Patients with end-stage edly raising the mortality rate (6). This role in the early prediction of kidney func- renal disease (ESRD), defined as receiving underscores the need for earlier and tion decline (24), as indicated by its ability dialysis or renal transplantation or GFR improved risk stratification of these pa- to predict development of microalbumin- ,15 mL/min/1.73 m2, were excluded. tients in order to enable precipitated and uria in normoalbuminuric individuals with The study complied with the Declaration targeted treatment for prevention of type 2 diabetes (18). of Helsinki, and all activities, as well as the complications and death. However, suPAR is not without its research protocol, were approved by the It has previously been shown that in- controversies. Several studies have cor- local ethics committee. All patients gave dividuals with type 1 diabetes generally related higher suPAR levels with de- informed written consent. exhibit a high state of inflammation and creased kidney function, and another oxidative stress (7), in part due to the has shown that estimated glomerular Analyses at Baseline autoimmunological nature of the disease filtration rate (eGFR) does not affect suPAR was measured using Conformite´ (7), which in turn has been associated suPAR in urine or circulation (25–28). Europeenne´ and in vitro diagnostic– with a sizable component in the develop- Although none of the studies show a approved suPARnostic ELISA kits (Viro- ment of micro- and macroangiopathy (8). causal association between kidney func- Gates, Birkerød, Denmark) according Therefore, it is of interest to investigate tion and suPAR, it can be measured in to the manufacturer’s protocol. Quanti- and target inflammatory biomarkers and urine, which is cause for prudence when fication of suPAR was available for all their pathways in hopes of better pre- evaluating the biomarker in individuals 667 patients. LDL cholesterol, serum diction and treatment of type 1 diabetes. with impaired kidney function. creatinine, and HbA1c were specified One of the proposed entry points is Aiming further attention at suPAR’s from venous blood samples using stan- soluble urokinase plasminogen activator prognostic aptitude, Eapen et al. (14) dardized methods. Urinary albumin ex- receptor (suPAR), an emerging bio- have shown that individuals with a suPAR cretion rate (UAER) was determined in marker associated with a myriad of in- level $3.5 ng/mL at baseline had a haz- three consecutive 24-h urine collections flammatory pathways (9). It originates ard ratio (HR) of 3.2 for the development and analyzed with enzyme immunoassay from urokinase plasminogen activator of myocardial infarction, and an HR of 2.6 (Vitros, Raritan, NJ). eGFR was calculated receptor (uPAR), a membrane receptor for cardiac mortality, compared with using the Chronic Kidney Disease Epide- expressed mainly on immune (10) and individuals with a level ,3.5. Another miology Collaboration (CKD-EPI) equa- endothelial cells (11), which during in- study found the risk of new-onset di- tion based on serum creatinine. CRP flammation is released in circulation in its abetes in a nonsmoking population of levels were measured using a particle- soluble form, suPAR (12). Current meth- middle-aged individuals to be 3.5 times enhanced immunoturbidimetry hs-CRP ods of determining inflammatory status higher in participants in the highest quar- assay (Roche/Hitachi, Group Communi- commonly use C-reactive protein (CRP), tile of suPAR compared with the lowest, cations, Basel, Switzerland). Levels of which is widely applied in several clinical after comprehensive adjustment (17). suPAR and CRP were measured after disciplines to assess inflammation and The existing knowledge indicates one thawing cycle, and samples were severity of disease (13). However, the suPAR as being a potent risk factor in stored at 280°C until analysis. stability and unspecificity of suPAR may various conditions, indicating possible Participants were categorized as nor- allow for a broader assessment of the clinical applications for risk stratification moalbuminuric if UAER was ,30 mg/24 h, inflammatory state, as it has been cor- in certain patient groups. However, the as microalbuminuric if UAER was or pre- related with the development of several clinical value has not been robustly re- viously had been recorded between pathological conditions, e.g., cardiovas- solved in several populations, including 30 and 299 mg/24 h, and as macroalbu- cular disease (14,15), mortality (16), patients with type 1 diabetes. Therefore, minuric if UAER was or previously had type 2 diabetes (16,17), DKD (18), cancer in this study, we analyze the predictive been recorded $300 mg/24 h in two out (19), and sepsis (20), in addition to qualities of suPAR in relation to the of three consecutive measurements. All being a strong marker of mortality and development of cardiovascular events, patients classified as normoalbuminuric admission time in acutely admitted med- development and progression of renal did not have any history of micro- or ical patients (20,21). As such it has been impairment, and mortality in patients macroalbuminuria prior to enrollment shown to be an attractive biomarker with type 1 diabetes. in the study. for use in both general risk stratification settings and for treatment optimiza- RESEARCH DESIGN AND METHODS Follow-Up tion of patients, in chronic outpatient Participants In 2016, patients were traced through the settings as well
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