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Major Adverse Kidney Events Are Associated with the Aquaporin 5 -1364A/C Promoter Polymorphism in Sepsis: A Prospective Validation Study.

ABSTRACT: Since the functionally important AQP5 -1364A/C single nucleotide promoter polymorphism alters key mechanisms of inflammation and survival in sepsis, it may affect the risk of an acute kidney injury. Accordingly, we tested the hypothesis in septic patients that this AQP5 polymorphism is associated with major adverse kidney events and also validated its impact on 90-day survival. In this prospective observational monocentric genetic association study 282 septic patients were included and genotyped for the AQP5 -1364A/C polymorphism (rs3759129). The primary endpoint was the development of major adverse kidney events within 30 days. In AC/CC genotypes, major adverse kidney events were less frequent (41.7%) than in AA genotypes (74.3%; OR:0.34; 95%-CI: 0.18-0.62; p < 0.001). Ninety-day survival was also associated with the AQP5 polymorphism (p = 0.004), with 94/167 deaths (56.3%) in AA genotypes, but only 46/115 deaths (40.0%) in C-allele carriers. Multiple proportional hazard analysis revealed AC/CC genotypes to be at significantly lower risk for death within 90 days (HR: 0.60; 95%-CI: 0.42-0.86; p = 0.006). These findings confirm the important role of the AQP5 -1364A/C polymorphism as an independent prognostic factor in sepsis. Furthermore, we demonstrate a strong association between this AQP5 polymorphism and susceptibility for major adverse kidney events suggesting a promising characteristic in terms of precision medicine.

SUBMITTER: Bergmann L

PROVIDER: S-EPMC7226758 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Major Adverse Kidney Events Are Associated with the Aquaporin 5 -1364A/C Promoter Polymorphism in Sepsis: A Prospective Validation Study.

Bergmann Lars L Nowak Hartmuth H Siffert Winfried W Peters Jürgen J Adamzik Michael M Koos Björn B Rahmel Tim T

Cells 20200407 4

Since the functionally important <i>AQP5</i> -1364A/C single nucleotide promoter polymorphism alters key mechanisms of inflammation and survival in sepsis, it may affect the risk of an acute kidney injury. Accordingly, we tested the hypothesis in septic patients that this <i>AQP5</i> polymorphism is associated with major adverse kidney events and also validated its impact on 90-day survival. In this prospective observational monocentric genetic association study 282 septic patients were included ...[more]

PMID: 32272738

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Project description:Background and objectivesMajor adverse kidney events, a composite of death, new kidney replacement therapy, or persistent kidney dysfunction, is a potential patient-centered outcome for clinical trials in sepsis-associated kidney injury. We sought to determine the incidence of major adverse kidney events within 30 days and validate this end point in pediatric sepsis.Design, setting, participants, & measurementsWe conducted a retrospective observational study using the Pediatric Health Information Systems Plus database of patients >6 months to <18 years old with a diagnosis of severe sepsis/septic shock; orders for bacterial blood culture, antibiotics, and at least one fluid bolus on hospital day 0/1; and known hospital disposition between January 2007 and December 2011. The primary outcome was incidence of major adverse kidney events within 30 days. Major adverse kidney events within 30 days were validated against all-cause mortality at hospital discharge, hospital length of stay, total hospital costs, hospital readmission within 30 days and 1 year, and lowest eGFR between 3 months and 1 year after discharge. We reported incidence of major adverse kidney events within 30 days with 95% confidence intervals using robust SEM and used multivariable logistic regression to test the association of major adverse kidney events within 30 days with hospital costs and mortality.ResultsOf 1685 admissions, incidence of major adverse kidney events within 30 days was 9.6% (95% confidence interval, 8.1% to 11.0%), including 4.5% (95% confidence interval, 3.5% to 5.4%) death, 1.7% (95% confidence interval, 1.1% to 2.3%) kidney replacement therapy, and 5.8% (95% confidence interval, 4.7% to 6.9%) persistent kidney dysfunction. Patients with versus without major adverse kidney events within 30 days had higher all-cause mortality at hospital discharge (28% versus 1%; P<0.001), higher total hospital costs ($61,188; interquartile range, $21,272-140,356 versus $28,107; interquartile range, $13,056-72,697; P<0.001), and higher proportion with eGFR<60 ml/min per 1.73 m2 between 3 months and 1 year after discharge (19% versus 4%; P=0.001). Major adverse kidney events within 30 days was not associated with length of stay or readmissions.ConclusionsIn children with sepsis, major adverse kidney events within 30 days are common, feasible to measure, and a promising end point for future clinical trials.

Project description:BackgroundWhether early fluid accumulation is a risk factor for adverse renal outcomes in septic intensive care unit (ICU) patients remains uncertain. We assessed the association between cumulative fluid balance and major adverse kidney events within 30 days (MAKE30), a composite of death, dialysis, or sustained renal dysfunction, in such patients.MethodsWe performed a multicenter, retrospective observational study in 1834 septic patients admitted to five ICUs in three hospitals in Stockholm, Sweden. We used logistic regression analysis to assess the association between cumulative fluid balance during the first two days in ICU and subsequent risk of MAKE30, adjusted for demographic factors, comorbidities, baseline creatinine, illness severity variables, haemodynamic characteristics, chloride exposure and nephrotoxic drug exposure. We assessed the strength of significant exposure variables using a relative importance analysis.ResultsOverall, 519 (28.3%) patients developed MAKE30. Median (IQR) cumulative fluid balance was 5.3 (2.8-8.1) l in the MAKE30 group and 4.1 (1.9-6.8) l in the no MAKE30 group, with non-resuscitation fluids contributing to approximately half of total fluid input in each group. The adjusted odds ratio for MAKE30 was 1.05 (95% CI 1.02-1.09) per litre cumulative fluid balance. On relative importance analysis, the strongest factors regarding MAKE30 were, in decreasing order, baseline creatinine, cumulative fluid balance, and age. In the secondary outcome analysis, the adjusted odds ratio for dialysis or sustained renal dysfunction was 1.06 (95% CI 1.01-1.11) per litre cumulative fluid balance. On separate sensitivity analyses, lower urine output and early acute kidney injury, respectively, were independently associated with MAKE30, whereas higher fluid input was not.ConclusionsIn ICU patients with sepsis, a higher cumulative fluid balance after 2 days in ICU was associated with subsequent development of major adverse kidney events within 30 days, including death, renal replacement requirement, or persistent renal dysfunction.

Project description:BackgroundSeveral biomarkers of AKI have been examined for their ability to predict AKI before serum creatinine. Few studies have focused on using kidney biomarkers to better predict major adverse kidney events (MAKE), an increasingly used composite outcome in critical care nephrology research.MethodsSingle-center prospective study collecting blood and urine samples from critically ill patients with AKI Kidney Disease Improving Global Outcomes stage 2 or above, and matched controls from a single, tertiary care intensive care unit (ICU). Samples were collected at 24-48 hours after AKI diagnosis (patients) or ICU admission (controls), 5-7 days later, and 4-6 weeks after discharge for patients with AKI. The primary outcome of interest was MAKE at hospital discharge (MAKE-DC), consisting of the composite end point of death, RRT dependence, or a decrease in estimated glomerular filtration to <75% of baseline.ResultsSerum/urinary neutrophil gelatinase-associated lipocalin (NGAL), serum/urinary cystatin C, and urinary kidney injury molecule-1 early in the AKI or ICU course were all significantly higher in patients with MAKE-DC compared with those not experiencing MAKE-DC. Additionally, serum/urinary NGAL and serum cystatin C measurements at the first time point remained significantly associated with MAKE events at 3, 6, and 12 months. Serum cystatin C, and to a lesser extent serum NGAL, significantly improved upon a logistic regression clinical prediction model of MAKE-DC (AUROC 0.94 and 0.87 versus 0.83; P=0.001 and P=0.02, respectively). Patients without MAKE-DC experienced a greater decline in serum NGAL from first to second measurement than those patients experiencing MAKE-DC.ConclusionsEarly measures of kidney biomarkers in patients who are critically ill are associated with MAKE-DC. This relationship appears to be greatest with serum NGAL and cystatin C, which display additive utility to a clinical prediction model. Trending serum NGAL may also have utility in predicting MAKE-DC.

Project description:BackgroundIn sepsis patients, Type 2 Diabetes Mellitus (T2DM) was associated with an increased risk of kidney injury. Furthermore, kidney damage is among the dangerous complications, with a high mortality rate in sepsis patients. However, the underlying predictive model on the prediction of major adverse kidney events within 30 days (MAKE30) in sepsis patients with T2DM has not been reported by any study.MethodsA total of 406 sepsis patients with T2DM were retrospectively enrolled and divided into a non-MAKE30 group (261 cases) and a MAKE30 group (145 cases). In sepsis patients with T2DM, univariate and multivariate logistic regression analyses were conducted to identify independent predictors of MAKE30. Based on the findings of multivariate logistic regression analysis, the corresponding nomogram was constructed. The nomogram was evaluated using the calibration curve, Receiver Operating Characteristic (ROC) curve, and decision curve analysis. A composite of death, new Renal Replacement Therapy (RRT), or Persistent Renal Dysfunction (PRD) comprised MAKE30. Finally, subgroup analyses of the nomogram for 30-day mortality, new RRT, and PRD were performed.ResultsIn sepsis patients with T2DM, Mean Arterial Pressure (MAP), Platelet (PLT), cystatin C, High-Density Lipoprotein (HDL), and apolipoprotein E (apoE) were independent predictors for MAKE30. According to the ROC curve, calibration curve, and decision curve analysis, the nomogram model based on those predictors had satisfactory discrimination (AUC = 0.916), good calibration, and clinical application. Additionally, in sepsis patients with T2DM, the nomogram model exhibited a high ability to predict the occurrence of 30-day mortality (AUC = 0.822), new RRT (AUC = 0.874), and PRD (AUC = 0.801).ConclusionThe nomogram model, which is available within 24 hours after admission, had a robust and accurate assessment for the MAKE30 occurrence, and it provided information to better manage sepsis patients with T2DM.

Project description:BackgroundAcute kidney injury (AKI) survivors are at increased risk of major adverse kidney events (MAKEs), including chronic kidney disease (CKD), end-stage kidney disease (ESKD) and death. High-risk AKI patients may benefit from specialist follow-up, but factors associated with increased risk have not been reported.MethodsWe conducted a retrospective study of AKI patients admitted to a single centre between 2012 and 2016 who had a baseline estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 and were alive and independent of renal replacement therapy (RRT) at 30 days following discharge. AKI was identified using International Classification of Diseases, Tenth Revision codes and staged according to the Kidney Disease: Improving Global Outcomes criteria. Patients were excluded if they were kidney transplant recipients or if AKI was attributed to intrinsic kidney disease. We performed Cox regression models to examine MAKEs in the first year, defined as the composite of CKD (sustained 25% drop in eGFR), ESKD (requirement for chronic RRT or sustained eGFR <15 mL/min/1.73 m2) or death. We examined secondary outcomes (CKD, ESKD and death) using Cox and competing risk regression analyses.ResultsWe studied 2101 patients (mean ± SD age 69 ± 15 years, baseline eGFR 72 ± 23 mL/min/1.73 m2). Of these, 767 patients (37%) developed at least one MAKE (429 patients developed CKD, 21 patients developed ESKD, 375 patients died). MAKEs occurred more frequently with older age [hazard ratio (HR) 1.16 per decade, 95% confidence interval (CI) 1.10-1.24], greater severity of AKI (Stage 2 HR 1.38, 95% CI 1.16-1.64; Stage 3 HR 1.62, 95% CI 1.31-2.01), higher serum creatinine at discharge (HR 1.04 per 10 µmol/L, 95% CI 1.03-1.06), chronic heart failure (HR 1.41, 95% CI 1.19-1.67), liver disease (HR 1.68, 95% CI 1.39-2.03) and malignancy (non-metastatic HR 1.44, 95% CI 1.14-1.82; metastatic HR 2.26, 95% CI 1.80-2.83). Traditional risk factors (e.g. diabetes and cardiovascular disease) had limited predictive value.ConclusionsMore than a third of AKI patients develop MAKEs within the first year. Clinical variables available at the time of discharge can help identify patients at increased risk of such events.

Dataset Information

Major Adverse Kidney Events Are Associated with the Aquaporin 5 -1364A/C Promoter Polymorphism in Sepsis: A Prospective Validation Study.

Publications

Major Adverse Kidney Events Are Associated with the Aquaporin 5 -1364A/C Promoter Polymorphism in Sepsis: A Prospective Validation Study.

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