Protecting the kidney from cisplatin induced injury and progression to chronic kidney disease

This proposal is in response to PAR-21-329 “Clinical Characterization of Cancer Therapy-Induced Adverse Sequelae and Mechanism Based Interventional Strategies.” Cisplatin is prescribed as a first-line treatment in nearly 20% of tumor chemotherapies, but efficacy is hindered by dose-dependent nephrotoxicity. Thirty percent of cancer patients receiving cisplatin develop acute kidney injury (AKI), a rapid decline in kidney function. AKI not only contributes to substantial morbidity, but also dramatically increases risk of chronic kidney disease (CKD), a leading cause of mortality worldwide . There are no FDA-approved drugs for the treatment of cisplatininduced AKI-CKD. The ultimate goal of this work is to protect the kidney from cisplatin-induced AKI and prevent its progression to CKD to improve cancer cure rates and enhance quality of life for cancer survivors. This proposal employs a new more clinically relevant model of cisplatin-induced AKI-CKD that was developed in our laboratories, termed Repeated Low Dose Cisplatin (RLDC) that involves weekly low doses of cisplatin over four weeks ; cancer is included in the model as an important co-morbidity. This RLDC model induces kidney injury, fibrosis, and CKD (RLDC-AKI-CKD) reminiscent of the clinical condition. Data indicate that the presence of a distant tumor adversely alters kidney function and physiology independently, exacerbates RLDC-AKI-CKD, and, perhaps most importantly, compromises the effect of agents previously shown to be nephroprotective in non-cancer bearing animals treated with RLDC. These data indicate the existence of a previously unappreciated cancer-kidney crosstalk and provide rationale for further investigation into underlying mechanisms of RLDC-AKI-CKD. the Our preliminary data indicate a mechanistic role for kidney infiltrating and resident macrophages (KIRMs) in the cancer-kidney crosstalk and RLDC-AKI-CKD. Cancer-induced KIRM accumulation leads to an epithelial to mesenchymal transition that involves loss of key epithelial proximal tubule components including the sodium glucose co-transporter 2 (SGLT2) and the 5-HT1F receptor; FDA approved drugs that inhibit SGLT2 or act as agonists of the 5-HT1F receptor are protective in RLDC models without cancer, but are entirely ineffective in RLDC models that include cancer due to the KIRM-induced PT EMT and resulting loss of drug targets. This proposal tests the hypothesis that distant tumors increase KIRMs to induce PT EMT and fibrosis, thereby sensitizing the kidney to RLDC-AKI-CKD; depletion of KIRMs will restore the efficacy of drugs that protect the kidney from RLDC-AKI-CKD. We will (1) determine the role and mechanism of specific KIRM subpopulations in the cancer-kidney crosstalk and RLDC and (2) determine if therapeutic targeting of KIRMs restores the efficacy of nephroprotectants in RLDC-AKI-CKD. These studies will provide essential translational data for development of therapies to prevent long term cancer and chemotherapy-induced kidney sequalae.