PRIORITY

Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria

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 Obiettivo del progetto (Objective)

Patients with diabetes are at risk of developing diabetic nephropathy, which will ultimately result in the requirement for renal replacement therapy and is also associated with high cardiovascular morbidity and mortality. Detection of low concentrations of albuminuria in urine (microalbuminuria) is the current clinical standard for detecting those at significant risk and targeting preventive treatment. However, albuminuria is of low specificity at early stages of disease, and of considerable biological variability, hence a poor predictor at early stages of disease. In two independent studies we have demonstrated that urinary proteomics offers the prospect of detecting nephropathy earlier in the preclinical phase, enabling targeted treatment at an earlier stage. We propose to assess the potential of this technology to identify normoalbuminuric patients at risk and to target therapy with an aldosterone receptor antagonist (spironolactone) as add-on to recommended therapy including angiotensin converting enzyme (ACE) inhibition or angiotensin II receptor blockers (ARBs) according to national guidelines. We will test the following hypotheses: (1) urinary proteomics predicts progression of albuminuria (as a surrogate marker for the development of overt nephropathy) in a cohort of 3280 type 2 diabetic patients with normal urinary albumin excretion, and (2) early initiation of intensive preventive therapy directed by urinary proteomics reduces progression of albuminuria in those 20 % at high risk and thereby delay progression to overt nephropathy and spare treatment for those with low risk, paving the way of personalised medicine. This will be the first biomarker-directed therapy trial for primary prevention of diabetic kidney disease. Additional clinical and circulating biomarkers will be assessed and models to predict progression of albuminuria including clinical factors, biomarkers and proteomics will be developed.

Introduzione (Teaser)

Diabetic patients often eventually develop kidney failure. EU researchers hope to identify such high-risk patients through the measurement of novel biomarkers.

Descrizione progetto (Article)

Nearly one in ten of European citizens suffer from diabetes and this number is expected to increase over the years. One of the common outcomes of type 2 diabetes is kidney damage which manifests with microalbuminuria, a condition characterised by protein excretion in the urine.

To prevent end stage renal disease, prevention of microalbuminuria is considered as the only solution. However, late diagnosis of the condition hampers the effective administration of preventive measures. Identifying individuals with risk of developing microalbuminuria would significantly help to reduce the chances of end stage renal disease.

The EU-funded http://www.eu-priority.org (PRIORITY) project will identify urinary biomarkers of type 1 and type 2 diabetes, as well as diagnostic biomarkers of chronic kidney disease. The rationale is that prompt identification of high-risk patients would facilitate the implementation of an intervention strategy.

In a multicentre study, the consortium will analyse over 3 500 type 2 diabetic patients and stratify them according to low or high risk of developing microalbuminuria. Low-risk patients will continue on standard care while high-risk patients will be given spironolactone, a drug that treats fluid retention in patients with kidney failure. To facilitate the study, an electronic patient registry has been set up at all thirteen clinical sites that will also be used for randomisation.

The very same proteomics markers have been used to perform meta-analysis of another patient study with great success. Prediction of microalbuminuria based on these biomarkers has been achieved for 740 diabetic patients.

The high predictive value of the PRIORITY biomarkers paves the way for their immediate clinical implementation. This would allow intervention before renal functional deterioration in diabetic patients, thereby significantly improving their quality of life.