Improved renal function after kidney transplantation is associated with heme oxygenase‐1 polymorphism

Abstract

Heme oxygenase-1 (HO-1) has a microsatellite polymorphism based on the number of guanosine-thymidine nucleotide repeats (GT) repeats that regulates expression levels and could have an impact on organ survival post-injury. We correlated HO-1 polymorphism with renal graft function. The HO-1 gene was sequenced (N = 181), and the allelic repeats were divided into subclasses: short repeats (S) (<27 repeats) and long repeats (L) (>/=27 repeats). A total of 47.5% of the donors carried the S allele. The allograft function was statistically improved six months, two and three yr after transplantation in patients receiving kidneys from donors with an S allele. For the recipients carrying the S allele (50.3%), the allograft function was also better throughout the follow-up, but reached statistical significance only three yr after transplantation (p = 0.04). Considering only those patients who had chronic allograft nephropathy (CAN; 74 of 181), allograft function was also better in donors and in recipients carrying the S allele, two and three yr after transplantation (p = 0.03). Recipients of kidney transplantation from donors carrying the S allele presented better function even in the presence of CAN.

Specific expression of heme oxygenase-1 by myeloid cells modulates renal ischemia-reperfusion injury

“…Therefore, we may postulate that myeloid HO-1 expression induced by hemin requires a critical level to be effective and that this minimal threshold in HO-1 expression was not reached in LT. By inference, the length polymorphism of guanosine thymidine dinucleotide (GT) n repeats in the promoter region of Hmox1 was associated with lower HO-1 activity 55 , mimicking the effect of a hypomorphic allele. Interestingly, longer (GT) n repeats in the Hmox1 promoter were associated with the occurrence of CKD and decreased renal function after cardiac surgery or kidney transplantation in humans 11, 56–58 . Also, it has been largely reported that hemin preconditioning significantly mitigates IRI-induced AKI 14, 15 .…”

Heme Oxygenase-1 in Kidney Health and Disease

“…Donor GT-repeat length was more important for renal function. Donors containing at least one S allele demonstrated better function over a 3-year follow-up period (107). HO is important for renal allograft function and survival, representing an avenue for therapeutic intervention.…”

“…Long polymorphisms, defined as greater than 25-27 repeats (L allele), in this region are associated with lower inducibility of HO-1 and increased risk of disease (14,27,30,107,148). Significant correlation with disease was identified in the settings of renal transplantation, diabetic kidney disease, CKD progression, AV fistula failure, and others (30,76,81,107,148). Recent evidence demonstrated microRNAs are involved in the regulation of human HO-1 expression in vitro (15).…”

Genetic Variations and Transplant Outcomes

“…Four SNPs within the same gene, tested in a single center study, were only significantly associated with time to rejection in preliminary analysis before correction for multiple testing [25]. One study found statistically improved allograft function up to 3 years after transplantation in patients receiving kidneys from donors as well as recipients with an HO-1 S allele [6]. …”

“…Lack of association was also seen in two studies using the (GT) n repeat. However, one set the cutoff at 25 instead of 27 GT repeats [5], and the other was small with 181 patients [6]. …”