Hemin pre-conditioning upregulates heme-oxygenase 1 in deceased donor renal transplant recipients and may offer protection: a randomised, controlled, phase IIB trial

Abstract Background: The enzyme heme oxygenase-1 (HO-1) degrades heme and protects against ischaemia-reperfusion injury (IRI), which is inevitable in transplantation. Monocytes/macrophages (MΦ) are the major source of HO-1 and higher levels improve renal transplant outcomes. Heme Arginate (HA) can safely induce HO-1 in humans. This randomised controlled trial evaluated the effect of HA on HO-1 upregulation and renal function in recipients of deceased donor kidneys. Methods: 40 recipients were randomised to either active (3mg kg-1 HA: pre-operatively and day 2) or placebo (NaCl: same schedule). Recipient blood was taken daily for peripheral blood mononuclear cells (PBMC) extraction. Urine was also collected. Graft biopsies were taken pre-op and day 5. Immunosuppression was standard. Results: HA upregulated PBMC HO-1 protein at 24 hours more than placebo: HA 11.1ng/ml vs. placebo 0.14ng/ml (p=<0.0001). PBMC HO-1 mRNA was also increased: HA 2.73 fold vs. placebo 1.41 fold (p=0.02). HA increased day 5 tissue HO-1 protein immunopositivity compared with placebo: HA 0.21 vs. placebo -0.03 (p=0.02) and % HO-1 positive renal MΦ also increased: HA 50.8 cells per hpf vs. placebo 22.3 (p=0.012). Urinary biomarkers were reduced after HA but not significantly so. Histological injury and renal function were similar but the study was not powered to these endpoints. Adverse events were equivalent between groups. Discussion: The primary outcome was achieved and demonstrated for the first time that HA safely induces HO-1 in renal transplant recipients. Larger studies are planned to determine the impact of HO-1 upregulation on clinical outcomes and evaluate the benefit to patients at risk of IRI.