Early detection of diabetic kidney disease by urinary proteomics and subsequent intervention with spironolactone to delay progression (PRIORITY): a prospective observational study and embedded randomised placebo-controlled trial.,The Lancet Diabetes & Endocrinology

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Early detection of diabetic kidney disease by urinary proteomics and subsequent intervention with spironolactone to delay progression (PRIORITY): a prospective observational study and embedded randomised placebo-controlled trial.
The Lancet Diabetes & Endocrinology ( IF 44.0 ) Pub Date : 2020-03-02 , DOI: 10.1016/s2213-8587(20)30026-7
Nete Tofte ₁ , Morten Lindhardt ₁ , Katarina Adamova ₂ , Stephan J L Bakker ₃ , Joachim Beige ₄ , Joline W J Beulens ₅ , Andreas L Birkenfeld ₆ , Gemma Currie ₇ , Christian Delles ₇ , Ingo Dimos ₈ , Lidmila Francová ₉ , Marie Frimodt-Møller ₁ , Peter Girman ₁₀ , Rüdiger Göke ₁₁ , Tereza Havrdova ₁₀ , Hiddo J L Heerspink ₁₂ , Adriaan Kooy ₁₃ , Gozewijn D Laverman ₁₄ , Harald Mischak ₁₅ , Gerjan Navis ₃ , Giel Nijpels ₁₆ , Marina Noutsou ₁₇ , Alberto Ortiz ₁₈ , Aneliya Parvanova ₁₉ , Frederik Persson ₁ , John R Petrie ₇ , Piero L Ruggenenti ₁₉ , Femke Rutters ₂₀ , Ivan Rychlík ₂₁ , Justyna Siwy ₁₅ , Goce Spasovski ₂₂ , Marijn Speeckaert ₂₃ , Matias Trillini ₁₉ , Petra Zürbig ₁₅ , Heiko von der Leyen ₂₄ , Peter Rossing ₂₅ ,

Affiliation

Steno Diabetes Center Copenhagen, Gentofte, Denmark.
University Clinic of Endocrinology, Diabetes and Metabolic Disorders, Skopje, Macedonia.
Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
Division of Nephrology and KfH Renal Unit, Hospital St Georg, Leipzig, Germany; Martin-Luther University Halle, Wittenberg, Germany.
Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands.
Department of Internal Medicine IV, Division of Endocrinology, Diabetology, and Nephrology, University Hospital Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich at Eberhard Karls University of Tübingen, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany.
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
Diabetespraxis, Leipzig, Germany.
1st Department, Charles University, Third Faculty of Medicine, Prague, Czech Republic.
Diabetes Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Diabetologische Schwerpunktpraxis, Diabetologen Hessen, Marburg, Germany.
Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
Bethesda Diabetes Research Center, Hoogeveen, Netherlands; Diabetes Vascular Research Foundation (DVRF), Hoogeveen, Netherlands; University Medical Center Groningen, Groningen, Netherlands.
Department of Internal Medicine/Nephrology, Ziekenhuisgroep Twente Hospital, Almelo, Netherlands.
Mosaiques Diagnostics, Hannover, Germany.
Department General Practice and Elderly Care, Amsterdam, Netherlands.
Diabetes Center, 2nd Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Hippokratio General Hospital, Athens, Greece.
Instituto de Investigacion Sanitaria de la Fundacion Jiménez Díaz UAM, Madrid, Spain.
Department of Renal Medicine, Clinical Research Centre for Rare Diseases "Aldo e CeleDaccò": Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Ranica, Bergamo, Italy.
Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, Netherlands.
1st Department, Charles University, Third Faculty of Medicine, Prague, Czech Republic; Faculty Hospital Královské Vinohrady, Prague, Czech Republic.
Department of Nephrology, Cyril and Methodius University in Skopje, Skopje, North Macedonia.
Department of Nephrology, Ghent University Hospital, Ghent, Belgium.
Hannover Clinical Trial Center, Hannover Medical School, Hannover, Germany.
Steno Diabetes Center Copenhagen, Gentofte, Denmark; University of Copenhagen, Copenhagen, Denmark.

Background

Microalbuminuria is an early sign of kidney disease in people with diabetes and indicates increased risk of cardiovascular disease. We tested whether a urinary proteomic risk classifier (CKD273) score was associated with development of microalbuminuria and whether progression to microalbuminuria could be prevented with the mineralocorticoid receptor antagonist spironolactone.

Methods

In this multicentre, prospective, observational study with embedded randomised controlled trial (PRIORITY), we recruited people with type 2 diabetes, normal urinary albumin excretion, and preserved renal function from 15 specialist centres in ten European countries. All participants (observational cohort) were tested with the CKD273 classifier and classified as high risk (CKD273 classifier score >0·154) or low risk (≤0·154). Participants who were classified as high risk were entered into a randomised controlled trial and randomly assigned (1:1), by use of an interactive web-response system, to receive spironolactone 25 mg once daily or matched placebo (trial cohort). The primary endpoint was development of confirmed microalbuminuria in all individuals with available data (observational cohort). Secondary endpoints included reduction in incidence of microalbuminuria with spironolactone (trial cohort, intention-to-treat population) and association between CKD273 risk score and measures of impaired renal function based on estimated glomerular filtration rate (eGFR; observational cohort). Adverse events (particularly gynaecomastia and hyperkalaemia) and serious adverse events were recorded for the intention-to-treat population (trial cohort). This study is registered with the EU Clinical Trials Register (EudraCT 20120-004523-4) and ClinicalTrials.gov (NCT02040441) and is completed.

Findings

Between March 25, 2014, and Sept 30, 2018, we enrolled and followed-up 1775 participants (observational cohort), 1559 (88%) of 1775 participants had a low-risk urinary proteomic pattern and 216 (12%) had a high-risk pattern, of whom 209 were included in the trial cohort and assigned to spironolactone (n=102) or placebo (n=107). The overall median follow-up time was 2·51 years (IQR 2·0–3·0). Progression to microalbuminuria was seen in 61 (28%) of 216 high-risk participants and 139 (9%) of 1559 low-risk participants (hazard ratio [HR] 2·48, 95% CI 1·80–3·42; p<0·0001, after adjustment for baseline variables of age, sex, HbA_1c, systolic blood pressure, retinopathy, urine albumin-to-creatinine ratio [UACR], and eGFR). Development of impaired renal function (eGFR <60 mL/min per 1·73 m²) was seen in 48 (26%) of 184 high-risk participants and 119 (8%) of 1423 low-risk participants (HR 3·50; 95% CI 2·50–4·90, after adjustment for baseline variables). A 30% decrease in eGFR from baseline (post-hoc endpoint) was seen in 42 (19%) of 216 high-risk participants and 62 (4%) of 1559 low-risk participants (HR 5·15, 95% CI 3·41–7·76; p<0·0001, after adjustment for basline eGFR and UACR). In the intention-to-treat trial cohort, development of microalbuminuria was seen in 35 (33%) of 107 in the placebo group and 26 (25%) of 102 in the spironolactone group (HR 0·81, 95% CI 0·49–1·34; p=0·41). In the safety analysis (intention-to-treat trial cohort), events of plasma potassium concentrations of more than 5·5 mmol/L were seen in 13 (13%) of 102 participants in the spironolactone group and four (4%) of 107 participants in the placebo group, and gynaecomastia was seen in three (3%) participants in the spironolactone group and none in the placebo group. One patient died in the placebo group due to a cardiac event (considered possibly related to study drug) and one patient died in the spironolactone group due to cancer, deemed unrelated to study drug.

Interpretation

In people with type 2 diabetes and normoalbuminuria, a high-risk score from the urinary proteomic classifier CKD273 was associated with an increased risk of progression to microalbuminuria over a median of 2·5 years, independent of clinical characteristics. However, spironolactone did not prevent progression to microalbuminuria in high-risk patients.

Funding

European Union Seventh Framework Programme.

中文翻译：

尿蛋白组学早期发现糖尿病肾病，随后用螺内酯干预以延缓病情发展（优先）：一项前瞻性观察研究和嵌入式安慰剂对照试验。

背景

微量白蛋白尿是糖尿病患者肾脏疾病的早期征兆，表明患心血管疾病的风险增加。我们测试了尿液蛋白质组学风险分类器（CKD273）评分是否与微量白蛋白尿的发展有关，以及盐皮质激素受体拮抗剂螺内酯是否可以预防向微量白蛋白尿的发展。

方法

在这项具有嵌入式随机对照试验（PRIORITY）的多中心，前瞻性，观察性研究中，我们招募了来自10个欧洲国家/地区的15个专科中心的2型糖尿病，尿白蛋白排泄正常且保留肾功能的患者。所有参与者（观察性队列）均使用CKD273分类器进行测试，并分为高风险（CKD273分类器评分> 0·154）或低风险（≤0·154）。被归类为高风险的参与者参加了一项随机对照试验，并使用交互式网络反应系统随机分配（1：1），以接受每日一次25 mg的螺内酯或相匹配的安慰剂（试验组）。主要终点是有可用数据的所有个体中确诊的微量白蛋白尿的发展（观察队列）。次要终点包括使用螺内酯（试验队列，意向性治疗人群）减少微量白蛋白尿的发生率，以及基于估计的肾小球滤过率（eGFR；观察性队列）的CKD273风险评分与肾功能受损程度之间的关联。记录了意向性治疗人群（试验队列）的不良事件（特别是妇科发育不良和高钾血症）和严重不良事件。该研究已在欧盟临床试验注册簿（EudraCT 20120-004523-4）和ClinicalTrials.gov（NCT02040441）中注册，并已完成。记录了意向性治疗人群（试验队列）的不良事件（特别是妇科发育不良和高钾血症）和严重不良事件。该研究已在欧盟临床试验注册簿（EudraCT 20120-004523-4）和ClinicalTrials.gov（NCT02040441）中注册，并已完成。记录了意向性治疗人群（试验队列）的不良事件（特别是妇科发育不良和高钾血症）和严重不良事件。该研究已在欧盟临床试验注册簿（EudraCT 20120-004523-4）和ClinicalTrials.gov（NCT02040441）中注册，并已完成。

发现

在2014年3月25日至2018年9月30日之间，我们招募并随访了1775名参与者（观察性队列），其中1559名参与者中的1559名（88％）具有低风险的尿蛋白质组学模式，而216名参与者（12％）具有高风险-风险模式，其中209人被纳入试验队列，并分配给螺内酯（n = 102）或安慰剂（n = 107）。总体中位随访时间为2·51年（IQR 2·0–3·0）。216名高风险参与者中有61名（28％）进展为微量白蛋白尿，1559名低风险参与者中有139名（9％）（危险比[HR] 2·48，95％CI 1·80-3·42；在调整了年龄，性别，HbA _1c，收缩压，视网膜病变，尿白蛋白与肌酐比值[UACR]和eGFR的基线变量后，p <0·0001 。肾功能损害的发展（eGFR <60 mL / min每1·73 m ²）出现在184名高风险参与者中的48名（26％）和1423名低风险参与者中的119名（8％）中（HR 3·50； 95％CI 2·50-4·90，校正基线变量后）。216名高风险参与者中的42（19％）和1559名低风险参与者中的62（4％）的eGFR与基线（事后终点）相比降低了30％（HR 5·15，95％CI 3 ·41–7·76； p <0·0001，针对基线eGFR和UACR进行调整后）。在意向性治疗试验队列中，安慰剂组107例中的35例（33％）和螺内酯组102例中的26例（25％）出现了微量白蛋白尿（HR 0·81，95％CI 0· 49–1·34； p = 0·41）。在安全性分析（意向性治疗队列研究）中，螺内酯组的102名参与者中有13名（13％）和4名（4％）的血浆钾浓度高于5·5 mmol / L。安慰剂组有107名参与者，螺内酯组中有三名（3％）参与者出现了女性乳腺发育不全，而安慰剂组中则没有。安慰剂组中有1名患者死于心脏事件（被认为可能与研究药物有关），螺内酯组中有1名患者死于癌症，被认为与研究药物无关。