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Immunohistochemical Detection of Hypoxia-Inducible Factor-1 in Human Renal Allograft Biopsies

Christian Rosenberger^*, Johann Pratschke, Birgit Rudolph, Samuel N. Heyman, Ralf Schindler^*, Nina Babel^*, Kai-Uwe Eckardt^||, Ulrich Frei^*, Seymour Rosen^¶ and Petra Reinke^*

^* Nephrology and Medical Intensive Care; Department of General, Visceral and Transplantation Surgery; Pathology, Charité Universitätsmedizin, Berlin, Germany; Department. of Medicine, Hadassah Mt. Scopus and the Hebrew University Medical School, Jerusalem, Israel; ^|| Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, Germany; and ^¶ Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts

Address correspondence to: Dr. Christian Rosenberger, Nephrology and Medical Intensive Care, Charité Universitätsmedizin, Virchow-Campus, Augustenburger Platz 1, 13353 Berlin, Germany. Phone: +49-30-450-553232; Fax: +49-30-450-553909; chrosenbe{at}aol.com

Received for publication July 26, 2006. Accepted for publication November 1, 2006.

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-1 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-1 is present and correlates with cold ischemic time >15 h and/or graft age >50 yr (P < 0.04). In contrast, a low HIF-1 score correlates with primary nonfunction, likely reflecting loss of oxygen consumption for tubular transport. Protocol biopsies at 2 wk show widespread HIF-1 induction, irrespective of histology. Beyond 3 mo, both protocol biopsies and indicated biopsies are virtually void of HIF-1, 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-1 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-1 immunohistochemistry could enhance the specific diagnosis of acute rejection.

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