Tandem 2: Functional Kidney Imaging across Scales

Short Summary:

In this tandem we use advanced live imaging techniques, such as two-photon microscopy, to increase knowledge of underlying molecular mechanisms in kidney diseases. Our aim is to identify new targets for therapeutic intervention in diseases where treatment options are currently limited.

Scope:

To use state of the art imaging techniques in rodent models and patients 1) to investigate kidney function (GFR, RBF, metabolism, structure); 2) to get novel insights into molecular mechanisms of kidney diseases; and 3) to evaluate new therapeutic modalities.

Specific Aims:

i) Tissue hypoxia and fibrosis are hallmarks of progression in chronic kidney disease (CKD). However, their CKD stage specific expression and interplay are not well defined. We will assess tissue oxygenation and fibrosis in relevant CKD mouse models and in CKD stage 1 to 5 patients using BOLD MRI. This approach will be used to evaluate potential protective effects of pharmacological compounds that influence tissue oxygenation and fibrosis. ii) Congenital and acquired dysfunction of renal proximal tubules (renal Fanconi syndrome, RFS) is associated with life-threatening metabolic complications in children and adults, with increased risk of developing CKD. The nature and sequence of events leading to the proximal tubule cell dysfunction is poorly defined. We will use PET, SPECT, fMRI and develop twophoton imaging in mouse models and patients to investigate the changes in filtration, secretion and reabsorption processes as well as the metabolic defects (glucose metabolism, reactive oxygen species production, mitochondrial function and structure) associated with RFS. iii) Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cystogenesis in both kidneys, leading to CKD and renal failure. Six million patients worldwide are affected and there is no treatment. Preliminary CT studies have indicated that loss of an intermediate non-cystic compartment of ADPKD kidneys predicts functional decline. However, this compartment is still ill-defined. We will use MRI to characterize this specific kidney compartment in mouse and rat models for ADPKD and evaluate its clinical relevance in our ADPKD cohort. Since disease progression in ADPKD is associated with abnormal osmoregulation and vasopressin signaling, we will assess the water balance and sodium distribution status of ADPKD mouse models and patients using Na23 MR imaging.

Scan Showing autosomal dominant polycystic kidney disease (ADPKD), one of the most common life-threatening genetic diseases, affecting more than 6 million people worldwide.

Molecular imaging techniques used:

MRI, BOLD-MRI, CT, Two-photon microscopy, SPECT, PET-MRI, Na23 MR.

Added value of KFSP for this specific tandem project:

Molecular imaging is a understudied area in research and care of kidney diseases. The project will allow knowledge and technology transfer from the advanced fields imaging. Established and well-documented mouse and rat models for kidney diseases and cohorts of patients (CKD, ADPKD, patients with inherited kidney diseases) are available.