title: Immunohistochemical detection of hypoxia-inducible factor-1alpha in human renal allograft biopsies.
abstract: Although it generally is accepted that renal hypoxia may occur in various situations after renal transplantation, direct evidence for such hypoxia is lacking, and possible implications on graft pathophysiology remain obscure. Hypoxia-inducible factors (HIF) are regulated at the protein level by oxygen-dependent enzymes and, hence, allow for tissue hypoxia detection. With the use of high-amplification HIF-1alpha immunohistochemistry in renal biopsies, hypoxia is shown at specific time points after transplantation with clinicohistologic correlations. Immediately after engraftment, in primarily functioning grafts, abundant HIF-1alpha is present and correlates with cold ischemic time >15 h and/or graft age >50 yr (P < 0.04). In contrast, a low HIF-1alpha score correlates with primary nonfunction, likely reflecting loss of oxygen consumption for tubular transport. Protocol biopsies at 2 wk show widespread HIF-1alpha induction, irrespective of histology. Beyond 3 mo, both protocol biopsies and indicated biopsies are virtually void of HIF-1alpha, with the only exception being clinical/subclinical rejection. HIF-derived transcriptional adaptation to hypoxia may counterbalance, at least partly, the negative impact of cold preservation and warm reflow injury. Transient hypoxia at 2 wk may be induced by hyperfiltration, hypertrophy, calcineurin inhibitor-induced toxicity, or a combination of these. Lack of detectable HIF-1alpha at 3 mo and beyond suggests that at this time point, graft oxygen homeostasis occurs. The strong correlation between hypoxia and clinical/subclinical rejection in long-term grafts suggests that hypoxia is involved in such graft dysfunction, and HIF-1alpha immunohistochemistry could enhance the specific diagnosis of acute rejection.
authors.affiliation: Nephrology and Medical Intensive Care, Charité Universitätsmedizin, Virchow-Campus, Augustenburger Platz 1, 13353 Berlin, Germany. chrosenbe@aol.com
authors.forename: Christian
authors.initials: C
authors.lastname: Rosenberger
authors.forename: Johann
authors.initials: J
authors.lastname: Pratschke
authors.forename: Birgit
authors.initials: B
authors.lastname: Rudolph
authors.forename: Samuel N
authors.initials: SN
authors.lastname: Heyman
authors.forename: Ralf
authors.initials: R
authors.lastname: Schindler
authors.forename: Nina
authors.initials: N
authors.lastname: Babel
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Eckardt
authors.forename: Ulrich
authors.initials: U
authors.lastname: Frei
authors.forename: Seymour
authors.initials: S
authors.lastname: Rosen
authors.forename: Petra
authors.initials: P
authors.lastname: Reinke
mesh_terms: D000328:Adult; D001706:Biopsy; D006084:Graft Rejection / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects / Q000473:pathology / Q000502:physiology*; D008875:Middle Aged; D013997:Time Factors
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit