SUN-043 ENDOTHELIAL NITRIC OXIDE SYNTHASE (ENOS) GENE POLYMORPHISM IN MALARIA ASSOCIATED ACUTE KIDNEY INJURY

Abstract

In endemic areas like odisha state in India, the incidence of AKI (acute kidney injury) may be >4% of malaria cases. The ENOS(Endothelial Nitric Oxide Synthase) derived NO (nitric oxide) mediates vasodilation, inhibits platelet aggregation and and modulates expression of cell adhesion molecules. We hypothesize that functionally important variants of ENOS could influence individual susceptibility to malaria associated AKI by altering the amount of NO generated by the endothelium. Plasma levels of nitric oxide will help in predicting malarial AKI Study was conducted between November 2018 to september 2019. Consecutive patients with acute kidney injury were included in the study. Clinically suspected malaria patients were screened for plasmodium falciparum infection using rapid diagnostic test, thick and thin film method and confirmed by species-specific PCR diagnosis. Venous blood were collected in EDTA-containing vials after informed consent was obtained from all enrolled patients (for analysis of ENOS gene polymorphism and plama nitric oxide level) and immediately centrifuged for 3 min. AKI were staged into 3 stages based on severity according to KDIGO criteria. ENOS gene polymorphism and plasma nitric oxide level measured in malaria associated AKI patients and were compared with other groups of AKI. Patients were followed for monthly basis to determine the course of the disease and progression of renal failure 128 patients with febrile illness associated with AKI were enrolled in the study. Around 38 had malarial AKI. 19 of them were stage 3 AKI. 16 of them underwent hemodialysis. 8 underwent intermittent hemodialysis more than 2 weeks. One patient expired. Of 30 patients who were followed up to 3 months, none developed CKD. We genotyped three commonly defined polymorphic loci of eNOS, Glu298->Asp, intron 4 variable number of tandem repeat region, and T-7863C, in these patients. The median plasma nitric oxide was found to be increased in individuals with the Glu298->Asp substitution and was significantly raised in mild malarial AKI (P < 0.0001), but the increase was not significant in stage 3 malarial AKI. When the genotype and allele frequencies for the three polymorphic sites ofthe eNOS gene (Glu298->Asp, intron 4 VNTR, and T-786->C) were compared for the groups of patients with mild and severe malarial AKI, a significant difference was observed only for Glu2983Asp polymorphism. In patients with mild malarial AKI, the Glu2983Asp substitution is associated with a significant difference in the median plasma NO levels. In patients with severe malaria with the Glu2983Asp substitution, the median plasma NO level was higher for the genotype with the T allele, but the difference was not statistically significant. Our findings suggest that the eNOS Glu298->Asp substitution enhance ENOS expression and NO production and thus have protective effects against malaria associated AKI. Median plasma nitric oxide level were significantly not increased in patients with stage 3 malarial AKI compared to other stages of AKI. These findings will increase our understanding of the pathogenesis of malaria associated AKI,