Hemin Preconditioning Upregulates Heme Oxygenase-1 in Deceased Donor Renal Transplant Recipients: A Randomized, Controlled, Phase IIB Trial

BACKGROUNDThe enzyme heme oxygenase-1 (HO-1) degrades heme and protects against ischemia-reperfusion injury. Monocytes/macrophages are the major source of HO-1 and higher levels improve renal transplant outcomes. Heme arginate (HA) safely induces HO-1 in humans. METHODSThe Heme Oxygenase-1 in renal Transplantation study was a randomized, placebo-controlled, IIb trial to evaluate HA effect on HO-1 upregulation after deceased donor kidney transplantation. 40 recipients were randomized to either 3 mg kg HA or placebo (0.9% NaCl), given preoperatively (day 0) and again on day 2. Recipient blood and urine were collected daily. Graft biopsies were taken preoperatively and on day 5. Primary outcome was HO-1 upregulation in peripheral blood mononuclear cells (PBMCs). Secondary outcomes were graft HO-1 upregulation and injury, urinary biomarkers, and renal function. RESULTSThe HA upregulated PBMC HO-1 protein more than placebo at 24 hoursHA 11.1 ng/mL versus placebo 0.14 ng/mL (P = < 0.0001). The PBMC HO-1 messenger RNA also increasedHA 2.73-fold versus placebo 1.41-fold (P = 0.02). Heme arginate increased day 5 tissue HO-1 protein immunopositivity compared with placeboHA 0.21 versus placebo −0.03 (P = 0.02) and % HO-1–positive renal macrophage also increasedHA 50.8 cells per high power field versus placebo 22.3 (P = 0.012). Urinary biomarkers were reduced after HA but not significantly. Histological injury and renal function were similar but the study was not powered for this. Adverse events were equivalent between groups. CONCLUSIONSThe primary outcome was achieved and demonstrated for the first time that HA safely induces HO-1 in transplant recipients. Planned larger studies will determine the impact of HO-1 upregulation on clinical outcomes and evaluate the benefit to patients at risk of ischemia-reperfusion injury.