PeRsOnalising Treatment Of Diabetic Nephropathy: (PROTON)

PeRsOnalising Treatment Of Diabetic Nephropathy: From Albuminuria to Multidimensional Characterisation of Diabetic Nephropathy - a Cross-sectional Study

Background: Today diabetic nephropathy is a frequent, and the most lethal and costly complication of diabetes. Although treating blood pressure with agents blocking renin angiotensin system has improved outcome, the prognosis is still poor and no new interventions have been successful during the past decade. There is an urgent need for discovery of new pathways behind the development and progression of diabetic nephropathy as well as of biomarkers which can identify subjects at risk of developing adverse events. Objective: By using a multidimensional 'omics' approach, we aim to search for novel proteins, metabolites and pathways that will point to the putative new mechanisms which underlie the early renal decline.

Design: Cross-sectional study, with long-term register-based follow-up. Study population: 160 patients with type 1 diabetes recruited from Steno Diabetes Center Copenhagen stratified based on stage of diabetic kidney disease, and 50 healthy non-diabetic controls. Endpoints: Primary endpoint: Glycocalyx thickness, assessed as perfused boundary region. Secondary endpoints: Gut microbiome characterisation and markers of gastrointestinal inflammation, autonomic and periphery neuropathy, urine and plasma Flow Cytometry Analysis (FACS), metabolomics and proteomics in plasma and urine, and other potential biomarkers.

Study Overview

• Status: Completed
• Conditions: Diabetes Complications; Diabetes Mellitus, Type 1; Diabetic Nephropathies

Detailed Description

Design: Cross-sectional study, with long-term register-based follow-up. Study population: 160 patients with type 1 diabetes recruited from Steno Diabetes Center Copenhagen stratified based on stage of diabetic kidney disease, and 50 healthy non-diabetic controls. Endpoints: Primary endpoint: Glycocalyx thickness, assessed as perfused boundary region. Secondary endpoints: Gut microbiome characterisation and markers of gastrointestinal inflammation, autonomic and periphery neuropathy, urine and plasma Flow Cytometry Analysis (FACS), metabolomics and proteomics in plasma and urine, and other potential biomarkers.

• Study Type: Observational
• Enrollment (Actual): 210

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen
    • Gentofte, Copenhagen, Denmark, 2820
      • Steno Diabetes center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

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.

Description

Inclusion Criteria:

• Patients with type 1 diabetes
• Written informed consent must be provided before participation
• Male or female patients >18 years of age with a diagnosis of type 1 diabetes (WHO criteria)
• Persistent urinary albumin creatinine ratio (UACR) assessed from EPJ (Electronic Patient Journal):
• < 30 mg/g in 2 out of 3 consecutive samples (normoalbuminuria)
• 30 - 299 mg/g in 2 out of 3 consecutive samples (microalbuminuria)

• ≥ 300 mg/g in 2 out of 3 consecutive samples (macroalbuminuria) - at least 30 with concurrent eGFR < 60 ml/min/1.73m2

  2. Control subjects without diabetes

• Written informed consent must be provided before participation.
• Male or female patients >18 years of age without a diagnosis of diabetes (assessed by Hb1Ac, haemoglobin and creatinine)

Exclusion Criteria: (Both subjects with and without diabetes)

• Non-diabetic kidney disease as indicated by medical history and/or laboratory findings
• Renal failure (eGFR<15 ml/min/1.73m2), dialysis or kidney transplantation
• Change in RAAS blocking treatment during the last month
• Treatment with antibiotics during the last 2 month
• Pregnancy or breastfeeding (urine HCG is performed on all fertile women)
• Patients who, in the judgement of the investigator, is incapable to participate
• For controls: Other diseases or intake of medicine which in the judgement of the investigator could affect the results, specifically renal, cardiovascular or inflammatory/infectious diseases should be considered for exclusion

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Type 1 DM, Normo albuminuric; Type 1 diabetics with no history of albumnuria (UACR < 30 mg/g in 2 out of 3 consecutive samples)
Type 1 DM, Micro albuminuric; Type 1 diabetics with history of micro albumnuria (UACR 30-299 mg/g in 2 out of 3 consecutive samples)
Type 1 DM, Macro albuminuric; Type 1 diabetics with history of macro albumnuria (UACR 30-299 mg/g in 2 out of 3 consecutive samples)
Healthy subjects; Subjects with no history of diabetes, other diseases or intake of medicine which in the judgement of the investigator could affect the results, specifically renal, cardiovascular or inflammatory/infectious diseases should be considered for exclusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The microvascular function by estimating the glycocalyx thickness	Glycocalyx thickness assessed as perfused boundary region by a hand-hold camera (GlycoCheck)	2019

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gut microbiome	Characterisation of the gut microbiota and markers of gastrointestinal inflammation	2019
Urine and plasma Flow Cytometry Analysis (FACS)	cell types related to inflammation	2019
Metabolomics in plasma	metabolite risk score in plasma	2019
Metabolomics in urine	metabolite risk score in urine	2019
proteomics in urine	proteomic risk score in urine	2019
proteomics in plasma	proteomic risk score in plasma	2019
Autonomic neuropathy	beat to beat variation (R-R test) upon Deep breathing	2019
peripheral neuropathy	vibration perception threshold	2019

Collaborators and Investigators

• Sponsor: Peter Rossing
• Investigators: Study Chair: peter Rossing, Steno Diabetes Center Copenhagen

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2016
• Primary Completion (Actual): October 1, 2017
• Study Completion (Actual): April 1, 2018

Study Registration Dates

• First Submitted: April 10, 2018
• First Submitted That Met QC Criteria: April 16, 2018
• First Posted (Actual): April 26, 2018

Study Record Updates

• Last Update Posted (Actual): April 26, 2018
• Last Update Submitted That Met QC Criteria: April 16, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Urologic Diseases; Endocrine System Diseases; Diabetes Mellitus; Kidney Diseases; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetes Complications
• Other Study ID Numbers: 36000

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No