CKD combination therapy beyond dual RAS/SGLT2 inhibition

慢性肾脏疾病（CKD）是一项全球性的医学挑战，因为它影响了世界上高达10%的人口，当无法获得肾脏替代治疗时，它是致命的，因为它与高发病率、死亡率和护理费用相关。CKD的进展越来越不依赖于触发原因，因为残留的肾元仅通过适应过程提供必要的过滤、吸收和分泌性能，而适应过程本身又促进了肾元的进一步损失。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过滤压力下残留的肾单位，从而缓解CKD的进展。2020年10月，DAPA-CKD研究首次表明，非糖尿病性CKD也从阻断钠-葡萄糖共转运蛋白-2中获益，这为CKD的治疗提供了全新的可能性。但是下一代潜在的肾保护物质已经出现了。该项目将测试这些药物联合使用可以增加肾脏保护作用的假设，从而最大限度地延长肾脏剩余寿命（=无透析寿命）。与动脉高血压、自身免疫性或肿瘤疾病的治疗类似，残余肾单位的缓解和结构保护方面的叠加效应应该通过同时阻断各种病理机制来实现，以长期稳定剩余的肾脏。这个项目的重点是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、恩格列净和其他创新化合物（包括ROCK抑制剂、HDAC抑制剂、生酮食品补充剂、gsk -3 β抑制剂和一种白细胞介素）在Alport肾病小鼠模型中对硬主要终点“肾脏存活”的影响。二次分析将处理冗余或附加的作用机制。最有效的组合应该有资格进行进一步的临床评估。

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.