Renal immune surveillance and dipeptidase-1 contribute to contrast-induced acute kidney injury

J Clin Invest. 2018 Jul 2;128(7):2894-2913. doi: 10.1172/JCI96640. Epub 2018 Jun 4.


Radiographic contrast agents cause acute kidney injury (AKI), yet the underlying pathogenesis is poorly understood. Nod-like receptor pyrin containing 3-deficient (Nlrp3-deficient) mice displayed reduced epithelial cell injury and inflammation in the kidney in a model of contrast-induced AKI (CI-AKI). Unexpectedly, contrast agents directly induced tubular epithelial cell death in vitro that was not dependent on Nlrp3. Rather, contrast agents activated the canonical Nlrp3 inflammasome in macrophages. Intravital microscopy revealed diatrizoate (DTA) uptake within minutes in perivascular CX3CR1+ resident phagocytes in the kidney. Following rapid filtration into the tubular luminal space, DTA was reabsorbed and concentrated in tubular epithelial cells via the brush border enzyme dipeptidase-1 in volume-depleted but not euvolemic mice. LysM-GFP+ macrophages recruited to the kidney interstitial space ingested contrast material transported from the urine via direct interactions with tubules. CI-AKI was dependent on resident renal phagocytes, IL-1, leukocyte recruitment, and dipeptidase-1. Levels of the inflammasome-related urinary biomarkers IL-18 and caspase-1 were increased immediately following contrast administration in patients undergoing coronary angiography, consistent with the acute renal effects observed in mice. Taken together, these data show that CI-AKI is a multistep process that involves immune surveillance by resident and infiltrating renal phagocytes, Nlrp3-dependent inflammation, and the tubular reabsorption of contrast via dipeptidase-1.

Keywords: Chronic kidney disease; Inflammation; Innate immunity; Macrophages; Nephrology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / etiology*
  • Acute Kidney Injury / immunology
  • Acute Kidney Injury / metabolism
  • Animals
  • Contrast Media / adverse effects*
  • Contrast Media / pharmacokinetics
  • Dipeptidases / metabolism*
  • Disease Models, Animal
  • GPI-Linked Proteins / metabolism
  • Humans
  • Immunologic Surveillance*
  • Inflammasomes / drug effects
  • Inflammasomes / immunology
  • Inflammasomes / metabolism
  • Kidney / drug effects
  • Kidney / enzymology*
  • Kidney / immunology*
  • Leukocytes / immunology
  • Leukocytes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein / deficiency
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology
  • Phagocytes / immunology
  • Phagocytes / metabolism


  • Contrast Media
  • GPI-Linked Proteins
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Dipeptidases
  • dipeptidase 1