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Thrombomodulin gene polymorphism and the occurrence and prognostic value of sepsis acute kidney injury.

ABSTRACT:

Abstract

To investigate the relationship between thrombomodulin (THBD) gene single nucleotide polymorphisms (SNPs) and susceptibility to sepsis and the occurrence and prognosis of acute kidney injury (AKI) in sepsis patients.The genotypes of THBD gene rs1962, rs3176123, and rs1042580 in 178 sepsis patients with AKI, 243 sepsis patients without AKI (No AKI), and 103 healthy controls were analyzed by direct sequencing. Enzyme-linked immunosorbent assay (ELISA) was used to detect the plasma THBD protein levels. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic value of plasma THBD levels in sepsis, AKI, and death of sepsis patients.The C allele carriers of THBD gene rs1962 were more likely to develop AKI and sepsis than the T allele carriers (OR = 1.61, 95% CI: 1.18-2.19, P < .01; OR = 2.16, 95% CI: 1.42-3.29, P < .01). The rs3176123 G allele was associated with an increased risk of AKI in sepsis patients (OR = 1.41, 95% CI: 1.06-1.88, P = .02), the G allele had a significant association with a higher risk of sepsis susceptibility (OR = 1.91, 95% CI: 1.33-2.75, P < .01). Sepsis patients of rs1042580 C allele had a lower risk of AKI than those of T allele (OR = 0.58, 95% CI: 0.37-0.91, P = .02), the C allele was related to a reduced risk of sepsis susceptibility (OR = 0.38, 95% CI: 0.26-0.55, P < .01). The THBD gene rs1962, rs3176123, and rs1042580 TGT haplotype was linked to higher risk of AKI in patients with sepsis (OR = 1.96, 95%CI: 1.14-3.38, P = .02). Sepsis patients with the THBD gene rs1962 TC + CC genotype had a higher risk of death than those with TT genotype (OR = 10.93, 95%CI: 5.05-26.96, P < .01), but there was no significant difference in the risk of death in sepsis patients with different genotypes at rs3176123 and rs1042580 (P > .05).The THBD gene rs1962, rs3176123, and rs1042580 SNPs are significantly associated with sepsis susceptibility and the risk of AKI. The rs1962 SNP is related to the risk of death in sepsis patients.

SUBMITTER: Li Q

PROVIDER: S-EPMC8257907 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionMatrix metalloproteinase-9 (MMP-9) plays an important role in the pathophysiology of sepsis. A single-nucleotide polymorphism (SNP) at position -1562 (C/T) in the MMP-9 gene has been associated with differential MMP-9 expression, being higher when the -1562 T allele is present. We evaluated the association of the SNP MMP9 -1562 C/T with severity and mortality in patients with sepsis to establish whether the prognosis of the disease is affected.Materials and methodsA case-control study exploratory was carried out in a cohort of infected patients. 540 individuals were selected in total, 270 patients with sepsis and 270 controls (infected but non-septic), classified according to the 2016 consensus (Sepsis-3). The presence of the single-nucleotide polymorphism (SNP; allele T and/or allele C) was determined through analyses of restriction fragment length polymorphism and plasma levels of MMP-9 were determined through enzyme-linked immunosorbent assay immunoassay.ResultsSNP MMP-9 -1562 has two known alleles (T and C), with predominance of the C over the T allele; in the group of patients with sepsis, T allele was found in 7.2% of cases, while C allele in the rest (92.8%); in comparison, in the group of infected but non-septic patients, frequencies were 9.4% for T allele and 90.6% for the C allele (P = .33). Also, the presence of the polymorphic T allele was not related to the levels of MMP-9 in patients with sepsis in comparison with infected but non-septic patients 780 (397-1375) ng/mL vs 646 (172-1249) ng/mL (P = .64). There was also no association between the SNP and sepsis mortality (P = .78).ConclusionsWe concluded that there was no association between the SNP MMP9 -1562 C/T and sepsis or between the SNP MMP9 -1562 C/T and sepsis mortality in the Northeastern Colombian septic patient cohort. Further research is needed to clarify the correlation among sepsis, genetic factors with allele T and MMP-9 plasma concentration.

Project description:BackgroundAcute hyperglycemia has been recognized as a robust predictor for occurrence of acute kidney injury (AKI) in nondiabetic patients with acute myocardial infarction (AMI), however, its discriminatory ability for AKI is unclear in diabetic patients after an AMI. Here, we investigated whether stress hyperglycemia ratio (SHR), a novel index with the combined evaluation of acute and chronic glycemic levels, may have a better predictive value of AKI as compared with admission glycemia alone in diabetic patients following AMI.MethodsSHR was calculated with admission blood glucose (ABG) divided by the glycated hemoglobin-derived estimated average glucose. A total of 1215 diabetic patients with AMI were enrolled and divided according to SHR tertiles. Baseline characteristics and outcomes were compared. The primary endpoint was AKI and secondary endpoints included all-cause death and cardiogenic shock during hospitalization. The logistic regression analysis was performed to identify potential risk factors. Accuracy was defined with area under the curve (AUC) by a receiver-operating characteristic (ROC) curve analysis.ResultsIn AMI patients with diabetes, the incidence of AKI (4.4%, 7.8%, 13.0%; p < 0.001), all-cause death (2.7%, 3.6%, 6.4%; p = 0.027) and cardiogenic shock (4.9%, 7.6%, 11.6%; p = 0.002) all increased with the rising tertile levels of SHR. After multivariate adjustment, elevated SHR was significantly associated with an increased risk of AKI (odds ratio 3.18, 95% confidence interval: 1.99-5.09, p < 0.001) while ABG was no longer a risk factor of AKI. The SHR was also strongly related to the AKI risk in subgroups of patients. At ROC analysis, SHR accurately predicted AKI in overall (AUC 0.64) and a risk model consisted of SHR, left ventricular ejection fraction, N-terminal B-type natriuretic peptide, and estimated glomerular filtration rate (eGFR) yielded a superior predictive value (AUC 0.83) for AKI.ConclusionThe novel index SHR is a better predictor of AKI and in-hospital mortality and morbidity than admission glycemia in AMI patients with diabetes.

Project description:BackgroundSepsis-associated acute kidney injury (SA-AKI) is associated with high morbidity, with no current therapies available beyond continuous renal replacement therapy (CRRT). Systemic inflammation and endothelial dysfunction are key drivers of SA-AKI. We sought to measure differences between endothelial dysfunction markers among children with and without SA-AKI, test whether this association varied across inflammatory biomarker-based risk strata, and develop prediction models to identify those at highest risk of SA-AKI.MethodsSecondary analyses of prospective observational cohort of pediatric septic shock. Primary outcome of interest was the presence of ≥ Stage II KDIGO SA-AKI on day 3 based on serum creatinine (D3 SA-AKI SCr). Biomarkers including those prospectively validated to predict pediatric sepsis mortality (PERSEVERE-II) were measured in Day 1 (D1) serum. Multivariable regression was used to test the independent association between endothelial markers and D3 SA-AKI SCr. We conducted risk-stratified analyses and developed prediction models using Classification and Regression Tree (CART), to estimate risk of D3 SA-AKI among prespecified subgroups based on PERSEVERE-II risk.ResultsA total of 414 patients were included in the derivation cohort. Patients with D3 SA-AKI SCr had worse clinical outcomes including 28-day mortality and need for CRRT. Serum soluble thrombomodulin (sTM), Angiopoietin-2 (Angpt-2), and Tie-2 were independently associated with D3 SA-AKI SCr. Further, Tie-2 and Angpt-2/Tie-2 ratios were influenced by the interaction between D3 SA-AKI SCr and risk strata. Logistic regression demonstrated models predictive of D3 SA-AKI risk performed optimally among patients with high- or intermediate-PERSEVERE-II risk strata. A 6 terminal node CART model restricted to this subgroup of patients had an area under the receiver operating characteristic curve (AUROC) 0.90 and 0.77 upon tenfold cross-validation in the derivation cohort to distinguish those with and without D3 SA-AKI SCr and high specificity. The newly derived model performed modestly in a unique set of patients (n = 224), 84 of whom were deemed high- or intermediate-PERSEVERE-II risk, to distinguish those patients with high versus low risk of D3 SA-AKI SCr.ConclusionsEndothelial dysfunction biomarkers are independently associated with risk of severe SA-AKI. Pending validation, incorporation of endothelial biomarkers may facilitate prognostic and predictive enrichment for selection of therapeutics in future clinical trials among critically ill children.

Project description:BACKGROUND:Currently, there are no reliable predictors of risk of development and severity of acute kidney injury (AKI) in septic patients. The surfactant protein D (SP-D) polymorphism rs721917C/T is associated with a greater susceptibility to AKI in the Chinese population. Our aim was to evaluate the value of SP-D polymorphisms rs721917C/T and of plasma SP-D levels to predict the risk of development of AKI (defined with KDIGO criterion) in septic patients. METHODS:The study enrolled septic patients admitted to the Critical Care Department of two tertiary care hospitals. SP-D rs721917C/T polymorphisms were determined using the PCR-SSP method. Plasma SP-D and urine NGAL contents were measured using commercially available ELISA kits. RESULTS:330 septic patients were included. Their SOFA scores were 12 ± 3. Patients with AKI (n = 156) had higher plasma SP-D levels (median: 153 ng/mL, range 111-198 ng/mL) and urinary NGAL levels (median: 575 ng/mL, range 423-727 ng/mL) than those without AKI (SP-D median: 124 ng/mL, range 81-159 ng/mL, P = 0.001; NGAL median: 484 ng/mL, range 429-573 ng/mL). Plasma SP-D levels of AKI patients were correlated with urinary NGAL contents (r = 0.853). In 32 patients receiving continuous renal replacement therapy (CRRT), plasma SP-D levels correlated with duration of CRRT (r = 0.448). The area under the receiver operating characteristic curve for plasma SP-D levels to predict AKI was 0.84. Patients with AKI had a higher rate of rs721917 CC genotype (AKI: 35% vs. non-AKI: 20%; P = 0.012), but a significantly lower rate of TT genotype (AKI: 19% vs. non-AKI: 26%; P = 0.005). SP-D rs721917 CC genotype was an independent predictor of AKI (P = 0.044) and mortality (P = 0.014). CONCLUSION:Our study showed that increased plasma SP-D level is associated with a higher risk of AKI in patients with sepsis. The SP-D rs721917CC genotype is an independent and significant predictor of AKI development and mortality of septic patients. The SP-D rs721917C/T polymorphisms should be further studied as diagnostic and prognostic biomarkers to facilitate early recognition of AKI.

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Thrombomodulin gene polymorphism and the occurrence and prognostic value of sepsis acute kidney injury.

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