CKD combination therapy beyond dual RAS/SGLT2 inhibition

慢性肾脏疾病(CKD)是一个全球性的医学挑战，因为它影响多达10%的世界人口，在无法获得肾脏替代治疗的情况下是致命的，而且它与高发病率、死亡率和护理费用相关。CKD的进展越来越独立于触发原因，因为残留的肾单位仅通过自身促进进一步肾单位丢失的适应过程提供必要的过滤、吸收和分泌能力。到目前为止，只有肾素-血管紧张素系统的抑制剂能够部分缓解滤过压下残留的肾单位，从而缓解CKD的进展。2020年10月，DAPA-CKD研究首次表明，非糖尿病CKD也从阻断钠-葡萄糖共转运体-2中受益良多，这为CKD的治疗提供了全新的可能性。但下一代潜在的肾脏保护物质已经可用。提出的项目将检验这样的假设，即这些药物的组合可以增加肾脏保护效果，从而最大限度地延长剩余肾脏寿命(=无需透析的寿命)。类似于治疗动脉高血压、自身免疫性疾病或肿瘤疾病，应通过同时阻断各种病理机制以长期稳定剩余肾脏，来达到缓解和保护残留肾单位的附加作用。这个项目的重点是那些已经被证明可以稳定肾上皮细胞结构和功能的化合物。为此，我们将测试雷米普利、埃帕利福秦和其他创新化合物的组合，包括岩石抑制剂、HDAC抑制剂、生酮食品补充剂、GSK-3β抑制剂和一种白介素类药物，以确定Alport肾病小鼠模型中的硬性主要终点“肾脏存活率”。二次分析将涉及多余或附加的行动机制。然后，最有效的组合应符合进一步的临床评估条件。

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.