New Insights Into Acute Kidney Injury: Infiltrating Myeloid Cell Heterogeneity and NF-κB Dependent Lymphatic Responses

Acute kidney injury (AKI) is one of the leading causes of death in hospitalized patients and presents significant challenges to the global healthcare system. Patients with a history of AKI are at greater risk of developing chronic kidney disease (CKD) and end-stage renal disease (ESRD). To date, there have been significant efforts undertaken to develop AKI therapeutics that have ultimately proven futile.

While our understanding of kidney resident macrophage (KRM) subpopulations and their functions have recently advanced, the dynamics of kidney infiltrating myeloid cells—particularly infiltrating macrophages (KIMs) and dendritic cells (KDCs)—remain largely unexplored. To characterize the temporal immune response, we utilized a myriad of advanced technologies, including single-cell RNA sequencing, spatial transcriptomics, CITE-seq, and flow cytometry.  

The lymphatic system has also recently emerged as a critical yet understudied component of kidney physiology, particularly during injury and following alterations in the kidney milieu. Here, we demonstrate the role of NF-kB in lymphatic remodeling and lymphangiogenesis following AKI by using a combination of biomolecular techniques alongside advanced tissue clearing and 3D imaging methodologies.

To develop novel kidney therapeutics, we must advance our understanding of the immune mechanisms involved in the injury response and the underlying molecular signaling pathways. An integrated approach examining the temporal dynamics of immune responses alongside the molecular mechanisms driving inflammation-induced lymphatic growth will illuminate the complex physiology of AKI. This will, in turn, help facilitate targeted drug discovery, potentially yielding promising therapeutic interventions beyond supportive care and dialysis.