PROTON: PeRsOnalising Treatment Of diabetic Nephropathy: From albuminuria to multidimensional characterisation of diabetic nephropathy

Outcome of diabetic nephropathy has improved with treatment of blood pressure with agents blocking renin angiotensin system, but the prognosis is still poor. It is clear, especially in light of recent disappointments in drug and treatment development in this area, that a more detailed understanding of the diversity of diabetic renal complications is crucial to advance the field. Therefore, new targets for better interventions and markers for risk of side effects are urgently needed. 

In general, single marker strategies have pointed towards potential new candidates related to e.g. inflammation or growth factors, but only added very little to the already applied phenotypic characteristics of diabetic nephropathy including urinary albumin excretion, whereas an emerging interest in multimarker strategies have shown promising results, but still at an early stage. 

Therefore, a deep multidimensional phenotypic characterisation, including glycocalyx thickness in relation to gut microbiota and potential pathological biomarkers associated with initiation and progression of diabetic renal disease may allow for new intervention strategies and personalised treatment in the future based on specific disease mechanisms and biomarkers of the individual person.

Aim: By using a multidimensional ‘omics’ approach and a deep multidimensional phenotypic characterisation, we aim to search for novel proteins, metabolites and pathways that will point to the putative new mechanisms which underlie the early renal decline related to diabetic nephropathy.

Design and method

Proton is a cross-sectional study, with long-term register-based follow-up. 

We will include 160 patients with type 1 diabetes and different stages of diabetic nephropathy (50 with normoalbuminuria; 50 with microalbuminuria; and 60 with macroalbuminuria -including at least 30 with concurrent estimated Glomerular Filtration Rate (eGFR) < 60 ml/min/1.73m2) compared to 50 healthy non-diabetic controls.

Target group

This cross sectional study targets type 1 diabetes patients with different stages of diabetic nephropathy (from normo- to macroalbuminuria).

Expected ending and outcome

  • A detailed phenotyping of type 1 diabetes patients with or without progressive renal complications will enable an increased understanding of what determines individual development and progression of diabetic renal complications. 
  • Application of techniques such as intravital microscopy of endothelial glycocalyx, DNA sequencing of bacteria in the gut, plasma and urine metabolomics, Flow Cytometry Analysis (FACS) of blood and urine cell subsets, and plasma and urine proteomics will enhance understanding of the diverse pathology in diabetic nephropathy with different stages compared to controls and will promote sub-classification of patients.
  • Findings from all these areas can be integrated to identify new targets and thus fully develop and test a more individualised treatment intervention based on detailed sub-classification of each diabetic patient.
Collaborators 
The PROTON consortium consisting of
  • Folkhälsan Research Center/FinnDiane Biomedicum, Helsinki, Finland
  • Universitair Medisch Centrum Groningen, The Nederlands 
  • -Joslin Diabetes Center, USA
  • The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of metabolic Genetics, University of Copenhagen   
  • Novo Nordisk A/S, Diabetes Complications Research, Måløv, Denmark
  • Mosaiques Diagnostics and Therapeutics AG, Germany 

Sidst opdateret 13-05-2016

Responsible
Signe Abitz Winther 
MD, PhD student

Peter Rossing
MD, professor