CKD combination therapy beyond dual RAS/SGLT2 inhibition

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Chronic kidney disease (CKD) is a global medical challenge because it affects up to 10% of the world population, it is fatal when there is no access to kidney replacement therapy, and because it is associated with high morbidity, mortality, and care costs. The progression of CKD becomes increasingly independent of the triggering cause, because the remnant nephrons only provide the necessary filtration, resorption and secretion performance through adaptation processes that on its own promote further nephron loss. So far, only inhibitors of the renin-angiotensin system have been able to partially relieve the residual nephrons from filtration pressure and thereby alleviate CKD progression. In October 2020 the DAPA-CKD study showed for the first time that non-diabetic CKD also benefits substantially from blocking the sodium-glucose cotransporter-2, which offers completely new possibilities for the treatment of CKD. But the next generation of potentially nephroprotective substances is already available.The project presented will test the hypothesis that combinations of these drugs can increase the nephroprotective effect and thus maximize the remaining kidney lifespan (= dialysis-free life). Analogous to the treatment of arterial hypertension, autoimmune or tumor diseases, additive effects with regard to the relief and structural protection of the residual nephrons should be achieved through simultaneous blockade of various pathomechanisms to stabilize the remaining kidney long term. The focus of this project is on compounds that were already shown to stabilize the structure and function of renal epithelial cells.For this purpose, we will test combinations of ramipril, empagliflozin and other innovative compounds including a ROCK Inhibitor, an HDAC Inhibitor, a ketogenic food supplement, a GSK-3beta Inhibitor, and one interleukin with regards to the hard primary endpoint “kidney survival” in the mouse model of Alport nephropathy. Secondary analyses will address the redundant or additive mechanisms-of-action. The most effective combination should then qualify for further clinical evaluation.