A prospective study on serum Cytokeratin (CK)-18 and CK18 fragments as biomarkers of acute hepato-intestinal GVHD

Leukemia. 2018 Dec;32(12):2685-2692. doi: 10.1038/s41375-018-0183-0. Epub 2018 Jun 27.


Apoptotic intestinal crypt cells are pathognomonic of acute intestinal graft versus host disease (GVHD). Serum levels of the apoptotic degradation product cytokeratin-18 fragments (CK18F) were associated with acute hepato-intestinal GVHD. Here we present a prospective clinical observational trial (NCT00935324) investigating serum levels of total CK18 (tCK18) and apoptotic CK18F to predict imminent acute hepato-intestinal GVHD and response to treatment. Total (t)CK18 and CK18F kinetics were measured before transplantation and in weekly intervals thereafter. In total 109 patients were enrolled. Acute hepato-intestinal GVHD grade I-IV was suspected in 36 patients (33%) at a median of 56 days post-transplant, 12 of these patients developed steroid-refractory GVHD. Both tCK18 and apoptotic CK18F increased at GVHD onset, and distinguished patients with suspected acute hepato-intestinal GVHD who were negative in intestinal histology. In patients with clinical acute hepato-intestinal GVHD, tCK18 significantly raised already 7-14 days before symptom onset. In receiver operator characteristics, areas under the curve at GVHD onset were 0.927 (p < 0.001) for tCK18 and 0.875 (p < 0.001) for apoptotic CK18F for patients with proven hepato-intestinal acute GVHD. This prospective study validates CK18F and highlights tCK18 as specific biomarkers suitable for improving prediction and diagnosis of suspected imminent and clinically manifest acute hepato-intestinal GVHD.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adult
  • Aged
  • Biomarkers / blood*
  • Female
  • Graft vs Host Disease / blood*
  • Hematopoietic Stem Cell Transplantation / methods
  • Humans
  • Intestines / pathology*
  • Keratin-18 / blood*
  • Liver / metabolism*
  • Male
  • Middle Aged
  • Prospective Studies
  • Transplantation, Homologous / methods
  • Young Adult


  • Biomarkers
  • KRT18 protein, human
  • Keratin-18