The underlying mechanisms leading to contrast-induced acute kidney injury (CI-AKI) are unclear. New findings demonstrate that CI-AKI involves a coordinated response between resident and infiltrating renal phagocytes and requires the tubular reabsorption of contrast media via the brush border enzyme dipeptidase 1. “One of the most important findings was the identification of the receptor that regulates the uptake of toxins from urine,” explains researcher Daniel Muruve. “These findings highlight the ability of the kidney to sample molecules filtered into the tubule and present them to the immune system.”

Following the observation that contrast induces an inflammatory response, Muruve and colleagues assessed the role of the immune sensor NLRP3 in CI-AKI. Administration of ioversol induced kidney injury in volume-depleted control mice, but Nlrp3–/– mice were protected from CI-AKI. Multiphoton intravital microscopy of reporter mice expressing GFP on cells of the myeloid lineage demonstrated the recruitment of GFP+ leukocytes before the onset of kidney injury in control, but not in Nlrp3–/–, mice. Interestingly, administration of contrast agent to cultured tubular epithelial cells caused cell death via a mechanism that was not dependent on NLRP3. Further studies demonstrated that rather than inducing tubular epithelial cell apoptosis, contrast-induced activation of the NLRP3 inflammasome occurred primarily in leukocytes, triggering an immune response.

To explore the mechanisms by which the kidney handles contrast, the researchers performed intravital microscopy imaging, demonstrating that contrast is rapidly taken up by resident phagocytes within the kidney. In volume depleted mice, contrast was also reabsorbed by tubular epithelial cells coinciding with leukocyte recruitment, with evidence of leukocytes actively taking up contrast material from epithelial cells before migrating away. “Our study highlights the importance of the kidney immune system in regulating injury,” notes Muruve. “Better understanding the interactions between resident and recruited immune cells with renal cells will open up new potential pathways for drug discovery specifically for kidney disease.”