@article{3077412,
    title = "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",
    author = "Tofte, N. and Lindhardt, M. and Adamova, K. and Bakker, S.J.L. and Beige, J. and Beulens, J.W.J. and Birkenfeld, A.L. and Currie, G. and Delles, C. and Dimos, I. and Francová, L. and Frimodt-Møller, M. and Girman, P. and Göke, R. and Havrdova, T. and Heerspink, H.J.L. and Kooy, A. and Laverman, G.D. and Mischak, H. and Navis, G. and Nijpels, G. and Noutsou, M. and Ortiz, A. and Parvanova, A. and Persson, F. and Petrie, J.R. and Ruggenenti, P.L. and Rutters, F. and Rychlík, I. and Siwy, J. and Spasovski, G. and Speeckaert, M. and Trillini, M. and Zürbig, P. and von der Leyen, H. and Rossing, P. and Zimmermann, S. and Rädisch, B. and Hävemeier, A. and Busmann, A. and Wittkop, U. and Neuhaus, B. and Ax-Smolarski, R. and Zieglschmid, V. and Bollweber, E. and Wölk, H. and Curovic, V.R. and Tougaard, N.H. and Eickhoff, M.K. and Pilemann-Lyberg, S. and Winther, S.A. and Rosenlund, S.V. and Hansen, T.W. and von Scholten, B.J. and Hansen, C.S. and Zobel, E.H. and Laursen, J.C. and Theilade, S. and Jelstrup, L. and Juhl, T.R. and Riis, D. and Hermann, J.A. and Lundgaard, A.G. and Halkjær, M.L.D. and Aabo, L. and Frost Lerche, T. and Lajer, M. and Stefansen, R.J. and Campbell, M.A. and Durban, A. and Raad, J. and Prigge, M. and Schiemann, M. and Wilson, R. and Kean, S. and Douglas, E. and Surtees, P. and Gant, C. and Yeung, S.M.H. and Hagedoorn, I. and Flynn, J. and Galloway, J. and Brooksbank, K. and Aparicio, C. and Iliev, I.P. and Nones, F. and Lo Bue, F. and Melacini, D. and Cugini, D. and Prandini, S. and Lecchi, V. and Yakymchuk, S. and Gherardi, G. and Villa, A. and Villa, D. and Gaspari, F. and Cannata, A.N. and Ferrari, S. and Stucchi, N. and Albrechtová, Š. and Eldeik, E. and Amanaki, R. and Fernandez-Fernandez, B. and Sanchez-Rodriguez, J. and Vázquez, C. and Sanz, A.B. and Sanchez-Niño, M.D. and Ramos, A.M. and Gonzalo, M.Á. and Schmidt, U. and Selim, G. and Gjorgovski, T. and Stratrova, S.S. and Stojceva-Taneva, O. and Schutten-Westerneng, P. and Wierbos, B. and Huvers, F. and De Bruin, A.K. and Lapauw, B. and de Man, E. and Rokegem, K. and Inion, S. and Kreutzmann, K. and Dewettinck, I. and Boukens-de Graaf, C. and Clerc-de Jong, F. and Entius, J. and Nannings, M. and van Steenderen, S. and Petry, F.W. and Kilic, C. and PRIORITY investigators",
    journal = "The Lancet Diabetes and Endocrinology",
    year = "2020",
    volume = "8",
    number = "4",
    pages = "301-312",
    publisher = "The Lancet Publishing Group",
    doi = "10.1016/S2213-8587(20)30026-7",
    keywords = "hemoglobin A1c;  placebo;  spironolactone;  mineralocorticoid antagonist;  spironolactone, adult;  age;  aged;  albumin to creatinine ratio;  Article;  cause of death;  chronic kidney failure;  classifier;  cohort analysis;  controlled study;  diabetic nephropathy;  disease course;  drug fatality;  drug safety;  estimated glomerular filtration rate;  European;  female;  follow up;  gynecomastia;  high risk population;  human;  hyperkalemia;  hypotension;  incidence;  kidney failure;  low risk population;  major clinical study;  male;  malignant neoplasm;  microalbuminuria;  multicenter study;  non insulin dependent diabetes mellitus;  observational study;  potassium blood level;  priority journal;  prospective study;  proteomics;  randomized controlled trial;  retinopathy;  sex;  systolic blood pressure;  urogenital system parameters;  albuminuria;  diabetic nephropathy;  disease exacerbation;  early diagnosis;  glomerulus filtration rate;  middle aged;  non insulin dependent diabetes mellitus;  pathophysiology;  proteomics;  treatment outcome;  urine, Adult;  Aged;  Albuminuria;  Diabetes Mellitus, Type 2;  Diabetic Nephropathies;  Disease Progression;  Early Diagnosis;  Female;  Glomerular Filtration Rate;  Humans;  Male;  Middle Aged;  Mineralocorticoid Receptor Antagonists;  Prospective Studies;  Proteomics;  Spironolactone;  Treatment Outcome",
    abstract = "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, HbA1c, 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. © 2020 Elsevier Ltd"
}