TUMOR NECROSIS FACTOR ALPHA PROMOTOR POLYMORPHISM AND SEVERITY OF ACUTE KIDNEY INJURY

Abstract

Background: Tumor necrosis factor alpha (TNFA) is a pro-inflammatory cytokine that has been implicated in the pathobiology of acute kidney injury (AKI). Methods: We explored the association of a functional polymorphism in the promoter region (rs1800629) of the TNFA gene with severity of AKI, as defined by levels of glomerular filtration rate (GFR) [serum cystatin C (using immunonephelometry technique) and serum creatinine (using Modified Jaffe method)] and tubular injury [urinary N-acetyl-β-D-glucosaminidase (NAG, using colorimetric assay) , kidney injury molecule-1 (KIM-1,using microsphere-based Luminex assay), alpha-glutathione s-transferase (alpha-GST, using sandwich ELISA), and pi-glutathione s-transferase (pi-GST ,using sandwich ELISA)] markers, in 262 hospitalized AKI adults. Results: In unadjusted analyses, TNFA GA- and AA-genotype groups had significantly higher peak (P=0.004), and discharge serum creatinine level (P=0.004), and enrollment serum cystatin C level (P=0.04) than TNFA GG-genotype. TNFA GA- and AA-genotype groups also had significantly higher urinary KIM-1 level (P=0.03), and urinary pi-GST level (P=0.03) when compared with the GG-genotype. After adjustment for sex, race, age, baseline estimated GFR, sepsis, and dialysis requirement, TNFA GA- and AA-genotype groups had a higher peak serum creatinine of 1.03 mg/dl (0.43, 1.63; P=0.001) and a higher urinary KIM-1 level (relative ratio 1.73; 95% CI 1.16, 2.59; P=0.008) when compared with the GG-genotype. TNFA GA- and AA-genotype groups also had a higher multiple organ failure score of 0.26 (95% CI 0.03, 0.49; P=0.024) after adjustment for sex, race, age, and sepsis when compared with the GG-genotype. Conclusions: The TNFA rs1800629 gene polymorphism is associated with markers of kidney disease severity and distant organ dysfunction among patients with AKI. Both monoclonal antibodies to TNF-alpha as well as soluble TNF receptors that can neutralize this cytokine and result in its biologically inactive form might be the novel treatment for AKI. Larger studies are needed to confirm these relationships and effect of new treatment on surrogate outcomes.