APOL1-Risk Genotype Induces Inflammatory and Hypoxic Gene Expression in Donor Kidneys

Area of Science:

• Nephrology
• Genetics
• Transplantation Immunology

Background:

• APOL1 renal-risk variants (RRVs) impact kidney disease and transplant outcomes.
• The effect of ischemia and preservation methods on APOL1 gene expression is not well understood.

Purpose of the Study:

• To investigate the impact of APOL1 RRVs on APOL1 gene expression in ischemic donor kidneys.
• To compare APOL1 and cytokine expression patterns between static cold storage (CS) and normothermic machine perfusion (NMP).

Main Methods:

• Paired deceased donor kidneys from donors of African ancestry were genotyped for APOL1 RRVs (G1 and G2).
• One kidney from each pair underwent 6 hours of NMP, while the contralateral kidney underwent 6 hours of CS.
• APOL1 gene expression, cytokine levels, and perfusion parameters were assessed.

Main Results:

• Significant differences in APOL1 gene expression were observed among G1/G0, G0/G0, and G2/G2 genotypes.
• APOL1 expression showed a significantly higher fold change under NMP in the G2/G2 genotype (2.4-fold).
• The inflammatory cytokine IFN-γ and KIM-1 were upregulated in G2/G2 kidneys, particularly under NMP.

Conclusions:

• High-risk APOL1 genotypes, especially G2/G2, exhibit increased APOL1 expression and inflammation, particularly with NMP.
• NMP can detect genotype-specific molecular changes in an ischemic reperfusion injury model.
• NMP shows potential for improved donor kidney assessment prior to transplantation.