Research and development

Regulation of body fluid homeostasis is of vital importance for all terrestrial organisms. In most mammals, the maintenance of the hydration status and normal plasma electrolytes levels critically depends on the appropriate handling of water and ions by the kidneys. This essential function involves specific transport systems operating in the epithelial cells lining kidney tubules. The study of these processes in various segments of the kidney, their regulation and ontogeny, and the pathophysiology of inherited renal disorders including tubulopathies and polycystic kidney disease, has provided essential information about the mechanisms of water and solute handling by the nephron in health and disease. Insights obtained through these investigations are relevant for common conditions such as blood pressure regulation, kidney stones, progression of renal failure, and cardiovascular complications of renal diseases.

The knowledge of transport mechanisms also led us to work on the molecular basis of water and solute transport across the peritoneal membrane, with the aim of improving peritoneal dialysis, a therapeutic modality for patients with end-stage renal disease. For instance, the group characterized innovative mouse and rat models of PD, established the influence of uremia and nitric oxide on the peritoneal membrane, documented the role of genetic factors to explain individual variability in transport parameters, substantiated the link between vascular proliferation and loss of ultrafiltration, contributed to delineate the role of water channels in PD, and depicted molecular mechanisms of the immune response during acute PD-related peritonitis and their impact on membrane integrity and transport.

Our research programs are based on a multi-disciplinary approach including studies on patients, human and mouse genetics, and analysis of mouse and cellular models. Over the years, our studies benefited from fruitful international collaborations, leading us to initiate and participate in several European networks. These collaborations allow us to develop our projects using genome, transcriptome and proteome analyses; genome-wide association studies; conditional KO and randomly mutagenized mice; in translation with studies of human tubular disorders collected at the European level.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and accounts for up to 10% of all patients on renal replacement therapy worldwide. It is characterized by relentless development and growth of cysts causing progressive kidney enlargement associated with hypertension, abdominal fullness and pain, episodes of cyst hemorrhage, gross hematuria, nephrolithiasis, cyst infections, and reduced quality of life. ADPKD is a systemic disorder affecting other organs with potentially serious complications such as massive hepatomegaly and intracranial aneurysm rupture. Mutations in the PKD1 (80-85%) and PKD2 (15-20%) genes account for the overwhelming majority of ADPKD cases.

The diagnosis of ADPKD relies primarily on imaging, although some cases are diagnosed by genetic testing. Typical imaging findings from patients with ADPKD reveal large kidneys with multiple bilateral cysts. Given its availability, safety, and low cost, ultrasonography is the imaging modality of choice for pre-symptomatic diagnosis. As kidney function may remain in the normal range despite severe destruction of the renal parenchyma, total kidney volume (TKV) is currently the best tool for monitoring and prognosticating in early stages of ADPKD. TKV, measured by magnetic resonance imaging or computed tomography, is an accurate estimate of kidney cyst burden and correlates with multiple kidney manifestations in ADPKD, such as pain, hypertension, hematuria, and proteinuria. TKV and cyst volume increase exponentially in all patients with ADPKD, but at variable rates (5%-6% per year on average). A classification of ADPKD has been developed based on age- and height-adjusted TKV.

Identifying patients at risk for progression is also important to select those who might benefit from novel therapeutic approaches specifically interfering with cyst growth and disease progression. Until recently, ADPKD has indeed been considered as an incurable disease, and its management only relied on early detection and treatment of hypertension, lifestyle modifications, treatment of renal and extra-renal complications, management of chronic kidney disease-related complications, and renal replacement therapy. In recent years, novel therapies have been developed and validated based on the improved understanding of ADPKD pathophysiology. Our group participated in the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes) 3:4 trial, an international randomized controlled trial which evaluated the effect of tolvaptan, a vasopressin V2 receptor antagonist, on ADPKD disease progression in 1445 ADPKD patients. Treatment with tolvaptan in patients with ADPKD with GFRs >60 mL/min and TKVs ≥ 750 mL showed significant effect on the rate of growth of TKV (-48%) and the rate of eGFR decline (-26%). Based on the findings of this landmark study, tolvaptan has been approved to delay the progression of ADPKD in patients with a rapid increase in TKV, and is now reimbursed in Belgium (September 2016).