Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy in TYpe 2 diabetic patients with normoalbuminuria (PRIORITY): essential study design and rationale of a randomised clinical multicentre trial

Morten Lindhardt, Frederik Persson, Gemma Currie, Claudia Pontillo, Joachim Beige, Christian Delles, Heiko von der Leyen, Harald Mischak, Gerjan Navis, Marina Noutsou, Alberto Ortiz, Piero Luigi Ruggenenti, Ivan Rychlik, Goce Spasovski, Peter Rossing, Morten Lindhardt, Frederik Persson, Gemma Currie, Claudia Pontillo, Joachim Beige, Christian Delles, Heiko von der Leyen, Harald Mischak, Gerjan Navis, Marina Noutsou, Alberto Ortiz, Piero Luigi Ruggenenti, Ivan Rychlik, Goce Spasovski, Peter Rossing

Abstract

Introduction: Diabetes mellitus affects 9% of the European population and accounts for 15% of healthcare expenditure, in particular, due to excess costs related to complications. Clinical trials aiming for earlier prevention of diabetic nephropathy by renin angiotensin system blocking treatment in normoalbumuric patients have given mixed results. This might reflect that the large fraction of normoalbuminuric patients are not at risk of progression, thereby reducing power in previous studies. A specific risk classifier based on urinary proteomics (chronic kidney disease (CKD)273) has been shown to identify normoalbuminuric diabetic patients who later progressed to overt kidney disease, and may hold the potential for selection of high-risk patients for early intervention. Combining the ability of CKD273 to identify patients at highest risk of progression with prescription of preventive aldosterone blockade only to this high-risk population will increase power. We aim to confirm performance of CKD273 in a prospective multicentre clinical trial and test the ability of spironolactone to delay progression of early diabetic nephropathy.

Methods and analysis: Investigator-initiated, prospective multicentre clinical trial, with randomised double-masked placebo-controlled intervention and a prospective observational study. We aim to include 3280 type 2 diabetic participants with normoalbuminuria. The CKD273 classifier will be assessed in all participants. Participants with high-risk pattern are randomised to treatment with spironolactone 25 mg once daily, or placebo, whereas, those with low-risk pattern will be observed without intervention other than standard of care. Treatment or observational period is 3 years.The primary endpoint is development of confirmed microalbuminuria in 2 of 3 first morning voids urine samples.

Ethics and dissemination: The study will be conducted under International Conference on Harmonisation - Good clinical practice (ICH-GCP) requirements, ethical principles of Declaration of Helsinki and national laws. This first new biomarker-directed intervention trial aiming at primary prevention of diabetic nephropathy may pave the way for personalised medicine approaches in treatment of diabetes complications.

Trial registration number: NCT02040441; Pre-results.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Figures

Figure 1
Figure 1
Study design. DM, diabetes mellitus.

References

    1. Gaede P, Vedel P, Larsen N et al. . Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383–93. 10.1056/NEJMoa021778
    1. Kramer HJ, Nguyen QD, Curhan G et al. . Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. JAMA 2003;289:3273–7. 10.1001/jama.289.24.3273
    1. Perkins BA, Ficociello LH, Roshan B et al. . In patients with type 1 diabetes and new-onset microalbuminuria the development of advanced chronic kidney disease may not require progression to proteinuria. Kidney Int 2010;77:57–64. 10.1038/ki.2009.399
    1. Fioretto P, Steffes MW, Mauer M. Glomerular structure in nonproteinuric IDDM patients with various levels of albuminuria. Diabetes 1994;43:1358–64. 10.2337/diab.43.11.1358
    1. Roscioni SS, Lambers Heerspink HJ, de Zeeuw D. Microalbuminuria: target for renoprotective therapy PRO. Kidney Int 2014;86:40–9. 10.1038/ki.2013.490
    1. Siwy J, Schanstra JP, Argiles A et al. . Multicentre prospective validation of a urinary peptidome-based classifier for the diagnosis of type 2 diabetic nephropathy. Nephrol Dial Transplant 2014;29:1563–70. 10.1093/ndt/gfu039
    1. Zürbig P, Jerums G, Hovind P et al. . Urinary proteomics for early diagnosis in diabetic nephropathy. Diabetes 2012;61:3304–13. 10.2337/db12-0348
    1. Brenner BM, Cooper ME, de Zeeuw D et al. . Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861–9. 10.1056/NEJMoa011161
    1. Lewis EJ, Hunsicker LG, Bain RP et al. . The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993;329:1456–62. 10.1056/NEJM199311113292004
    1. Lewis EJ, Hunsicker LG, Clarke WR et al. . Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851–60. 10.1056/NEJMoa011303
    1. Haller H, Ito S, Izzo JL Jr et al. . Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 2011;364:907–17. 10.1056/NEJMoa1007994
    1. Andrésdóttir G, Jensen ML, Carstensen B et al. . Improved survival and renal prognosis of patients with type 2 diabetes and nephropathy with improved control of risk factors. Diabetes Care 2014;37:1660–7. 10.2337/dc13-2036
    1. Rossing P. Prediction, progression and prevention of diabetic nephropathy. The Minkowski Lecture 2005. Diabetologia 2006;49:11–9. 10.1007/s00125-005-0077-3
    1. Schjoedt KJ, Andersen S, Rossing P et al. . Aldosterone escape during blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate. Diabetologia 2004;47:1936–9. 10.1007/s00125-004-1542-0
    1. Navaneethan SD, Nigwekar SU, Sehgal AR et al. . Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol 2009;4:542–51. 10.2215/CJN.04750908
    1. Rossing P. Proteomic Prediction and Renin Angiotensin Aldosterone System Inhibition Prevention Of Early Diabetic nephRopathy In TYpe 2 Diabetic Patients With Normoalbuminuria (PRIORITY). In: ClinicalTrialsgov[Internet] (NCT02040441) 2013.
    1. Mischak H, Vlahou A, Ioannidis JP. Technical aspects and inter-laboratory variability in native peptide profiling: the CE-MS experience. Clin Biochem 2013;46:432–43. 10.1016/j.clinbiochem.2012.09.025
    1. Neuhoff N, Kaiser T, Wittke S et al. . Mass spectrometry for the detection of differentially expressed proteins: a comparison of surface-enhanced laser desorption/ionization and capillary electrophoresis/mass spectrometry. Rapid Commun Mass Spectrom 2004;18:149–56. 10.1002/rcm.1294
    1. Stalmach A, Albalat A, Mullen W et al. . Recent advances in capillary electrophoresis coupled to mass spectrometry for clinical proteomic applications. Electrophoresis 2013;34:1452–64. 10.1002/elps.201200708
    1. Jantos-Siwy J, Schiffer E, Brand K et al. . Quantitative urinary proteome analysis for biomarker evaluation in chronic kidney disease. J Proteome Res 2009;8:268–81. 10.1021/pr800401m
    1. Girolami M, Mischak H, Krebs R. Analysis of complex, multidimensional datasets. Drug Discov Today Technol 2006;3:13–9. 10.1016/j.ddtec.2006.03.010
    1. Yang ZR, Chou KC. Bio-support vector machines for computational proteomics. Bioinformatics 2004;20:735–41. 10.1093/bioinformatics/btg477
    1. Good DM, Zürbig P, Argilés A et al. . Naturally occurring human urinary peptides for use in diagnosis of chronic kidney disease. Mol Cell Proteomics 2010;9:2424–37. 10.1074/mcp.M110.001917
    1. Alkhalaf A, Zürbig P, Bakker SJ et al. . Multicentric validation of proteomic biomarkers in urine specific for diabetic nephropathy. PLoS ONE 2010;5:e13421 10.1371/journal.pone.0013421
    1. Lindhardt M, Persson F, Zürbig P et al. . Urinary proteomics predict onset of microalbminuria in normoalbuminuric type 2 diabetic patients, a sub-study of the DIRECT 2 study. ASN 23, A213 2012.
    1. Mann JF, Rossing P, Wiecek A et al. . Diagnosis and treatment of early renal disease in patients with type 2 diabetes mellitus: what are the clinical needs? Nephrol Dial Transplant 2015;30(Suppl 4):iv1–5. 10.1093/ndt/gfv120
    1. Andersen S, Brochner-Mortensen J, Parving HH. Irbesartan in patients with type D, microalbuminuria study G. Kidney function during and after withdrawal of long-term irbesartan treatment in patients with type 2 diabetes and microalbuminuria. Diabetes Care 2003;26:3296–302. 10.2337/diacare.26.12.3296
    1. Ruggenenti P, Fassi A, Ilieva AP et al. . Preventing microalbuminuria in type 2 diabetes. N Engl J Med 2004;351:1941–51. 10.1056/NEJMoa042167
    1. Bilous R, Chaturvedi N, Sjolie AK et al. . Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. Ann Intern Med 2009;151:11–20, W3-4. 10.7326/0003-4819-151-1-200907070-00120
    1. Becker GJ, Hewitson TD, Chrysostomou A. Aldosterone in clinical nephrology—old hormone, new questions. Nephrol Dial Transplant 2009;24:2316–21. 10.1093/ndt/gfp256
    1. Epstein M. Aldosterone and the hypertensive kidney: its emerging role as a mediator of progressive renal dysfunction: a paradigm shift. J Hypertens 2001;19:829–42. 10.1097/00004872-200105000-00001
    1. Epstein M. Aldosterone as a determinant of cardiovascular and renal dysfunction. J R Soc Med 2001;94:378–83.
    1. Oxlund CS, Cangemi C, Henriksen JE et al. . Low-dose spironolactone reduces plasma fibulin-1 levels in patients with type 2 diabetes and resistant hypertension. J Hum Hypertens 2015;29:28–32. 10.1038/jhh.2014.27
    1. Rossing K, Schjoedt KJ, Smidt UM et al. . Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: a randomized, double-masked, cross-over study. Diabetes Care 2005;28:2106–12. 10.2337/diacare.28.9.2106
    1. Epstein M, Williams GH, Weinberger M et al. . Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J Am Soc Nephrol 2006;1:940–51. 10.2215/CJN.00240106
    1. Nielsen SE, Persson F, Frandsen E et al. . Spironolactone diminishes urinary albumin excretion in patients with type 1 diabetes and microalbuminuria: a randomized placebo-controlled crossover study. Diabet Med 2012;29:e184–90. 10.1111/j.1464-5491.2012.03585.x
    1. International Diabetes Federation. IDF diabetes atlas. 6th edn Brussels, Belgium: International Diabetes Federation., 2013, 2013.
    1. Li R, Bilik D, Brown MB et al. . Medical costs associated with type 2 diabetes complications and comorbidities. Am J Manag Care 2013;19:421–30.
    1. Kröpelin TF, de Zeeuw D, Andress DL et al. . Number and frequency of albuminuria measurements in clinical trials in diabetic nephropathy. Clin J Am Soc Nephrol 2015;10:410–16. 10.2215/CJN.07780814
    1. Parving HH, Persson F, Rossing P. Microalbuminuria: a parameter that has changed diabetes care. Diabetes Res Clin Pract 2015;107:1–8. 10.1016/j.diabres.2014.10.014
    1. Schmieder RE, Mann JF, Schumacher H et al. . Changes in albuminuria predict mortality and morbidity in patients with vascular disease. J Am Soc Nephrol 2011;22:1353–64. 10.1681/ASN.2010091001
    1. Schmieder RE, Schutte R, Schumacher H et al. . Mortality and morbidity in relation to changes in albuminuria, glucose status and systolic blood pressure: an analysis of the ONTARGET and TRANSCEND studies. Diabetologia 2014;57:2019–29. 10.1007/s00125-014-3330-9

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