SINGuLAR · SINGle-cell mapping of Living kidney donation for the Assessment of Renal adaptation

>850 million people are affected by kidney disease, which is caused by kidney injury. Following injury, kidney cells have a remarkable ability to adapt. Previous studies have largely focused on kidney injury signatures, yet treatments successfully targeting injury in animals have failed in humans. Studies focused not on injury but on adaptation are lacking. The main reason for this is that studying kidney adaptation with existing methods is challenging due to the low signal-to-noise ratio of adaptation in the presence of injury.Instead of studying adaptation in kidney injury patients, SINGuLAR will therefore study isolated adaptation in living kidney donors: Donors, who irreversibly lose 50% of their kidney mass and function, show astonishing compensatory growth and functional adaptation. Studying the remaining kidney after contralateral organ loss allows to leverage an unbiased system free from injury-related noise.Since tissue biopsies from remaining kidneys that adapt well put living donors at disproportionately high risk, SINGuLAR will use renal cells shed into urine to create the first prospective single-cell transcriptomic map of kidney adaptation (Aim1). Additionally, we will investigate whether remaining kidney adaptation is epigenetically wired (Aim2) and how this process is spatiotemporally patterned (Aim3). SINGuLAR will also assess whether multi-omic data from remaining kidneys in donors correlate with outcomes of donated partner organs in recipients (Aim4), and it will leverage urine-derived tubuloids to enable patient-specific drug targeting (Aim5).By employing the remaining kidney as a one-of-a-kind human model, SINGuLAR aims to obtain unprecedented spatiotemporal insights into the biology of kidney adaptation and compensatory growth, which can subsequently be harnessed to therapeutically enhance organ adaptation in future kidney injury contexts.