In 2017, on a world scale the total number of individuals with chronic kidney disease (CKD), acute kidney injury (AKI), and those on renal replacement therapy (RRT) exceeded 850 million, a truly concerning figure that is twice the estimated number of people with diabetes worldwide and >20 times higher than the number of individuals affected by AIDS/HIV worldwide (Jager KJ, Kidney Int. 2019). We aim to contribute to reduce the burden of kidney disease by focusing on the following topics.

1) Early and non-invasive detection of CKD. Late stage CKD is very difficult to treat and the "Holy Grail" remains early disease detection since standard of care medication, such as inhibitors of the renin angiotensin system, are generally quite effective in delaying the progression of the disease. In children, CKD is frequently related to abnormal kidney development, while in adults this essentially results from diabetes and aging. We focus on early disease detection using “omics” approaches to identify biomarkers in body fluids such as urine, blood and amniotic fluid. In addition to their contribution to early detection of CKD, these omics-related markers are also analyzed for the potential involvement in the pathophysiology of the disease using models systems. Our ultimate goal is to provide early CKD detection tests for the clinic, provide innovative therapeutic strategies and improve its management. To achieve these goals, we have access to several thousand samples and follow-up data of adult and pediatric patients and a wide panel of model systems.

2) Early detection of AKI and improvement of treatment. AKI is a common complication in hospitalized patients. It is associated with an increased risk of early and late mortality, as well as the development of CKD among survivors. The absence of AKI predictors (before renal aggression) and of early and robust AKI biomarkers (4 to 6 hours after aggression) do not allow to stratify the patients upstream or immediately after renal aggression and according to the risk of AKI. It is therefore essential to improve this stratification (in particular pre-aggression) in order to personalize the management and to offer a specific treatment only to patients at risk of or developing AKI. Such optimized stratification should also facilitate the identification of new treatments and reduce the number of patients to include in interventional clinical studies. It will finally identify a panel of biomarkers that can be used in humans or animals to promote the transferability of a molecule from animals to humans.

3) Reduce cardiovascular complications. CKD is associated with a very high risk of cardiovascular mortality (CV). However, the mechanisms of the cardiovascular complications of CKD are atypical and therefore still poorly understood. In particular, atheroma plaques in CKD patients are defined by the aberrant development of compromised blood vessels and micro-calcifications. In addition, cardiovascular lesions appear in a silent manner and are generally detected only at an advanced stage, at the time of the occurrence of a CV event. It is therefore essential to better understand the pathophysiology of CV complications, but also to identify at an early stage CKD patients at risk for CV complications in order to improve their management and to individualize their medical follow-up. This research is expected to improve the quality of life of many patients with CKD, allowing older people who are severely affected by this disease to age better.

Focus on omics. Much of our research is based on data obtained by omic approaches because it has been shown that complex pathologies, such as nephropathies, cannot be described by one or two markers only. We are therefore working towards the detection of molecular signatures of kidney disease that may be mono-omic (Decramer et al., Nat Med 2006, Klein et al., Sci Transl Med 2013) or multi-omic to further improve the description of this complex pathology. These omics approaches are also useful for: i) discovering new drugs through drug repositioning as we have recently shown (Schanstra et al., JCI-Insight 2019); ii) improve the translatability of preclinical observations by the generation of humanized non-invasive signatures in animals (Klein et al., Kidney Int 2016); iii) identify new targets both in the area of ​​cardiovascular complications and of renal development.

Humanization

Expected benefits
- Non-invasive diagnostic tests for early detection of kidney disease, progression and complications.
- Specific targets (drugs) and appropriate management to prevent the development and complications of kidney disease.