Macrophages as Potential Mediators of Lung Cancer-Kidney Cross-Talk

Background: Cisplatin (CDDP) is a widely used chemotherapeutic agent for solid organ cancers. However, its efficacy is hindered by dose-limiting nephrotoxicity. Thirty percent of cancer patients treated with CDDP develop acute kidney injury (AKI). AKI not only complicates cancer management but also increases the risk of chronic kidney disease (CKD). Despite promising preclinical studies, there is no FDA-approved treatment for CDDP-induced kidney injury (CDDP-KI). This is partly attributed to the reliance of preclinical studies on non-cancer models of CDDP-KI, which fail to capture the complex pathophysiology of cancer patients, thus compromising clinical relevance. Our group has recently demonstrated that lung cancer adversely affects kidney function and physiology and exacerbates CDDP-KI, indicating cancer-kidney crosstalk. However, the underlying mechanism driving this interaction remains unclear. Our preliminary data indicate an accumulation of renal macrophages concomitant with the pathological alterations in the kidney of lung cancer mice, implying their role in cancer-kidney crosstalk. We hypothesize that depleting macrophages attenuates cancer-induced nephrotoxicity. Methods: Eight-week-old B6;129 mice, with or without lung cancer, received three weekly doses of intravenous clodronate-encapsulated liposome (clodrosome) or saline-encapsulated liposome (encapsome) for 28 days. The kidney immune profile, injury, and fibrosis were then assessed. Results: Clodrosome efficiently depleted renal macrophages and prevented kidney injury, evidenced by decreased KIM-1 expression and preservation of the proximal tubular brush border membrane. Moreover, it reduced the production of extracellular matrix components and attenuated fibrosis. Conclusion: Our findings indicate that macrophages mediate cancer-induced nephrotoxicity and support further investigation into macrophage-based immunotherapy as a novel treatment for CDDP-KI within the context of cancer-kidney crosstalk. Funding: NIDDK Support