Early detection, molecular mechanisms and therapeutic interventions in chronic kidney disease

Introduction

The objective of ELIMINATE-CKD is to demonstrate that combining measures of kidney structure and function will strongly enhance detection of chronic kidney disease (CKD). To reach this objective, I will develop a new method to quantify the number of nephrons, the smallest functional units in the kidney.

Rationale

• CKD affects ~10% of the global population and causes 2.6 million deaths/year. CKD-associated costs (140 billion euros/year in Europe) exceed diabetes and cancer. Limitations in CKD detection impede the success of emerging therapies.
• Current CKD definition is based on creatinine-based estimated glomerular filtration rate, which is often inaccurate due to interindividual differences in body composition and compensation for early kidney damage as remaining nephrons increase their function.
• Using a unique combination of multi-omics and machine learning approaches in human cohorts and innovative animal models, I will dissect pathways that drive nephron number and enable its quantification.

Concrete Objectives

1. Develop a high-throughput method to quantify nephron number in large human cohorts and a novel rat model of gradual nephron reduction.
2. Construct and validate unbiased and hypothesis-driven nephron number algorithms based on kidney-derived proteins, lipids, and metabolites in blood and urine.
3. Demonstrate that nephron number algorithms enable earlier and more accurate CKD detection.
4. Provide proof of principle that nephron number-triggered therapy prevents or halts CKD.

Impact

This project will lead to a new CKD classification, based on both structure and function. Identification of mechanisms driving nephron number will boost drug development and regenerative medicine towards nephron-preserving therapies. Finally, the concept of structure-function relationship is relevant in many other organs (brain, heart). My passion to beat kidney disease by innovative diagnostics drives me towards my ultimate goal: to eliminate CKD.