Genetic variants in SERPINA4 and SERPINA5, but not BCL2 and SIK3 are associated with acute kidney injury in critically ill patients with septic shock.
ABSTRACT: Acute kidney injury (AKI) is a multifactorial syndrome, but knowledge about its pathophysiology and possible genetic background is limited. Recently the first hypothesis-free genetic association studies have been published to explore individual susceptibility to AKI. We aimed to replicate the previously identified associations between five candidate single nucleotide polymorphisms (SNP) in apoptosis-related genes BCL2, SERPINA4, SERPINA5, and SIK3 and the development of AKI, using a prospective cohort of critically ill patients with sepsis/septic shock, in Finland.This is a prospective, observational multicenter study. Of 2567 patients without chronic kidney disease and with genetic samples included in the Finnish Acute Kidney Injury (FINNAKI) study, 837 patients had sepsis and 627 patients had septic shock. AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria, considering stages 2 and 3 affected (severe AKI), stage 0 unaffected, and stage 1 indecisive. Genotyping was done using iPLEXTM Assay (Agena Bioscience). The genotyped SNPs were rs8094315 and rs12457893 in the intron of the BCL2 gene, rs2093266 in the SERPINA4 gene, rs1955656 in the SERPINA5 gene and rs625145 in the SIK3 gene. Association analyses were performed using logistic regression with PLINK software.We found no significant associations between the SNPs and severe AKI in patients with sepsis/septic shock, even after adjustment for confounders. Among patients with septic shock (252 with severe AKI and 226 without AKI (149 with KDIGO stage 1 excluded)), the SNPs rs2093266 and rs1955656 were significantly (odds ratio 0.63, p?=?0.04276) associated with stage 2-3 AKI after adjusting for clinical and demographic variables.The SNPs rs2093266 in the SERPINA4 and rs1955656 in the SERPINA5 were associated with the development of severe AKI (KDIGO stage 2-3) in critically ill patients with septic shock. For the other SNPs, we did not confirm the previously reported associations.
Project description:BACKGROUND AND OBJECTIVES: To promote early detection of AKI, recently proposed pretest probability models combine sub-Kidney Disease Improving Global Outcomes (KDIGO) AKI criteria with baseline AKI risk. The primary objective of this study was to determine sub-KDIGO thresholds that identify patients with septic shock at highest risk for AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a retrospective analysis of 390 adult patients admitted to the medical intensive care unit (ICU) of a tertiary, academic medical center with septic shock between January 2008 and December 2010. Hourly urine output was collected from the time of septic shock recognition (hour 0) to hour 96, urine catheter removal, or ICU discharge (whichever occurred first). All available serum creatinine (SCr) measurements were collected until hour 96. The AKI pretest probability model was assessed during the first 12 hours of resuscitation and included the initial episode of oliguria, increase from baseline to peak SCr level, and Acute Physiology and Chronic Health Evaluation (APACHE) III score in a multivariable receiver-operator characteristic (ROC) analysis. The primary outcome was the incidence of stage II or III (stage II+) AKI defined by KDIGO criteria. Secondary outcomes included the need for RRT and 28-day mortality. RESULTS: Ninety-eight (25%) patients developed stage II+ AKI after septic shock recognition. APACHE III score and increase in SCr level in the first 12 hours were not statistically associated with stage II+ AKI in multivariable ROC analysis. Consecutive oliguria for 3 hours had fair predictive ability for achieving stage II+ AKI criteria (area under ROC curve, 0.73; 95% confidence interval [95% CI], 0.68 to 0.78), and oliguria for 5 hours demonstrated optimal accuracy (82%; 95% CI, 79% to 86%). CONCLUSIONS: Three to 5 hours of consecutive oliguria in patients with septic shock may provide a valuable measure of AKI risk. Further validation to support this finding is needed.
Project description:<h4>Introduction</h4>Chronic kidney disease (CKD) and acute kidney injury (AKI) are strongly associated with excess morbidity and mortality and frequently co-occur in critically ill septic patients, but how their interplay affects clinical outcomes is not well elucidated.<h4>Methods</h4>We conducted a single-center, retrospective cohort study of 2632 adult patients admitted to the intensive care unit (ICU) with severe sepsis or septic shock. Subjects were classified into 6 groups according to baseline CKD (no-CKD: estimated glomerular filtration rate [eGFR] ?60; CKD: eGFR 15-59 ml/min per 1.73 m<sup>2</sup>) and incident AKI by the Kidney Disease: Improving Global Outcomes (KDIGO) serum creatinine criteria (no-AKI, AKI stage 1, AKI stages ?2) during ICU stay. Study outcomes were 90-day mortality (in hospital or within 90 days of discharge) and incident/progressive CKD.<h4>Results</h4>Prevalent CKD was 46% and incident AKI was 57%. Adjusted hazard ratios (95% confidence intervals) for 90-day mortality relative to the reference group of no-CKD/no-AKI were 1.5 (1.1-2.0) in no-CKD/AKI stage 1, 2.4 (1.9-3.1) in no-CKD/AKI stages?2, 1.1 (0.8-1.4) in CKD/no-AKI, 1.2 (0.9-1.6) in CKD/AKI stage 1, and 2.2 (1.7-2.9) in CKD/AKI stages ?2. A similar trend was observed for incident/progressive CKD during a median follow-up of 15.3 months.<h4>Conclusion</h4>Stage 1 AKI on CKD was not associated with an independent increased risk of adverse outcomes in critically ill septic patients. AKI stages ?2 on CKD and any level of AKI in no-CKD patients were strongly and independently associated with adverse outcomes. Sepsis-associated stage 1 AKI on CKD may represent distinct underlying pathophysiology, with more prerenal cases and less severe <i>de novo</i> intrinsic damage, which needs further investigation.
Project description:BACKGROUND:Acute kidney injury (AKI) is the most common extra-pulmonary organ failure in acute respiratory distress syndrome (ARDS). Renal recovery after AKI is determined by several factors. The objective of this study was to determine the predictors of renal non-recovery in ARDS patients. METHODS:A single center retrospective cohort study of patients with AKI after onset of ARDS. Patients with preexisting chronic kidney disease or intensive care unit stay < 24 h were excluded. AKI staging was defined according to the Kidney Disease Improving Global Outcomes (KDIGO) 2012 guidelines. Renal non-recovery was defined as death, dialysis dependence, serum creatinine ≥1.5 times the baseline, or urine output < 0.5 mL/kg/h more than 6 h. RESULTS:Of the 244 patients that met study criteria, 60 (24.6%) had stage I AKI, 66 (27%) had stage II AKI, and 118 (48.4%) had stage III AKI. Of those, 148 (60.7%) patients had renal non-recovery. On multivariable analysis, factors associated with renal non-recovery were a higher stage of AKI (odds ratio [OR] stage II 5.71, 95% confidence interval [CI] 2.17-14.98; OR stage III 45.85, 95% CI 16.27-129.2), delay in the onset of AKI (OR 1.12, 95% CI 1.03-1.21), history of malignancy (OR 4.02, 95% CI 1.59-10.15), septic shock (OR 3.2, 95% CI 1.52-6.76), and a higher tidal volume on day 1-3 of ARDS (OR 1.41, 95% CI 1.05-1.90). Subgroup analysis of survival at day 28 of ARDS also found that higher severity of AKI (OR stage II 8.17, 95% CI 0.84-79.91; OR stage III 111.67, 95% CI 12.69-982.91), delayed onset of AKI (OR 1.12, 95% CI 1.02-1.23), and active malignancy (OR 6.55, 95% CI 1.34-32.04) were significant predictors of renal non-recovery. CONCLUSIONS:A higher stage of AKI, delayed onset of AKI, a history of malignancy, septic shock, and a higher tidal volume on day 1-3 of ARDS predicted renal non-recovery in ARDS patients. Among survivors, a higher stage of AKI, delayed onset of AKI, and a history of malignancy were associated with renal non-recovery.
Project description:Purpose:To analyse the capacity of whole-blood NGAL (wbNGAL) to stratify AKI in critically ill patients with and without sepsis. Methods:Whole-blood NGAL was measured with a point-of-care device at admission and 48 hours later in patients admitted to a general ICU. Patients were classified by the AKIN and KDIGO classifications at admission and 24 and 48 hours. We performed an ROC curve analysis. wbNGAL values at admission were compared in patients with sepsis and septic shock. Results:The study included 100 consecutively admitted patients (40 female) with mean age 59.1 ± 17.8 years. Thirty-three patients presented AKI at admission, and 10 more developed it in the next 48?h. Eighteen patients had AKI stage 3, 14 of them at admission. Nine patients required renal replacement therapy. According to KDIGO at admission, wbNGAL values were 78??g/L (60-187) in stage 0 (n = 67), 263??g/L (89-314) in stage 1 (n = 8), 484??g/L (333-708) in stage 2 (n = 11), and 623??g/L (231-911) in stage 3 (n = 14), p = 0.0001 for trend. Ten patients did not complete 48 hours of study: 6 of 10 were discharged (initial wbNGAL 130??g/L (60-514)) and 4 died (773??g/L (311-1010)). The AUROC curve of wbNGAL to predict AKI was 0.838 (95% confidence interval 0.76-0.92, p = 0.0001), with optimal cut-off value of 178??g/L (sensitivity 76.7%, specificity 78.9%, p < 0.0001). At admission, twenty-nine patients had sepsis, of whom 20 were in septic shock. wbNGAL concentrations were 81??g/L (60-187) in patients without sepsis, 481 (247-687) in those with sepsis, and 623.5??g/L (361-798) in the subgroup of septic shock (p < 0.0001). Conclusions:Whole-blood NGAL concentration at ICU admission was a good stratifier of AKI in critically ill patients. However, wbNGAL concentrations were higher in septic patients irrespective of AKI occurrence.
Project description:Background:To examine whether the new urinary biomarkers TIMP2 and IGFBP7 can predict progression within 24 hours and 72 hours from mild and moderate (KDIGO 1 or 2) to severe (KDIGO 3) AKI in patients with septic shock. Methods:A prospective, multicenter observational study performed in three French ICUs. The urinary biomarkers TIMP2?IGFBP7 were analyzed at the early phase (<6 hours) of patients admitted for septic shock with mild and moderate AKI. Results:Among the 112 patients included, 45 (40%) progressed to the KDIGO 3 level 24 hours after inclusion (KDIGO 3 H24) and 47 (42%) 72 hours after inclusion (KDIGO 3 H72). The median urinary TIMP2?IGFBP7 at inclusion (baseline) were higher in the KDIGO 3 group than in the KDIGO<3 group at H24 and H72. All covariates with a p value < 0.1 in the univariate analysis were included in stepwise multiple logistic regression models to identify factors independently associated with the risk of KDIGO 3 at H24 and H72. TIMP2?IGFBP7 remained independently associated with KDIGO 3 at H24 and H72. Baseline posology of norepinephrine, baseline urine output, and baseline serum creatinine remained also significantly associated with progression to KDIGO 3 at H24. Baseline TIMP2?IGFBP7 and baseline urinary output had the best AUC ROC. A baseline TIMP2?IGFBP7 > 2.0 (ng/ml)2/1,000 identified the population at high risk of KDIGO 3 H24 (relative risk 4.19 (1.7-10.4)) with a sensitivity of 76% (60-87) and a specificity of 81% (69-89). But the diagnostic performance at H72 of baseline TIMP2?IGFBP7 was poor (AUC: 0.69 (0.59-0.77)). Conclusion:The urinary TIMP2?IGFBP7 concentration and the urine output at the early phase of septic shock are independent factors to identify the population at high risk of progression from mild and moderate to severe AKI over the next 24 but not 72 hours. A TIMP2?IGFBP7 concentration > 2.0 (ng/ml)2/1,000 quadruples the risk of KDIGO 3 AKI within 24 hours. This trial is registered with (NCT03547414).
Project description:(1) Background: Sepsis-associated acute kidney injury (AKI) can lead to permanent kidney damage, although the long-term prognosis in patients with septic shock remains unclear. This study aimed to identify risk factors for the development of chronic kidney disease (CKD) in septic shock patients with AKI. (2) Methods: A single-site, retrospective cohort study was conducted using a registry of adult septic shock patients. Data from patients who had developed AKI between January 2011 and April 2017 were extracted, and 1-year follow-up data were analysed to identify patients who developed CKD. (3) Results: Among 2208 patients with septic shock, 839 (38%) had AKI on admission (stage 1: 163 (19%), stage 2: 339 (40%), stage 3: 337 (40%)). After one year, kidney function had recovered in 27% of patients, and 6% had progressed to CKD. In patients with stage 1 AKI, 10% developed CKD, and mortality was 13% at one year; in patients with stage 2 and 3 AKI, the CKD rate was 6%, and the mortality rate was 42% and 47%, respectively. Old age, female, diabetes, low haemoglobin levels and a high creatinine level at discharge were seen to be risk factors for the development of CKD. (4) Conclusions: AKI severity correlated with mortality, but it did not correlate with the development of CKD, and patients progressed to CKD, even when initial AKI stage was not severe. Physicians should focus on the recovery of renal function, and ensure the careful follow-up of patients with risk factors for the development of CKD.
Project description:BACKGROUND:Continuous veno-venous hemodialysis with high cut-off membranes (HCO-CVVHD) removes inflammatory mediators involved in organ dysfunction during sepsis. The aim of the present study was to assess the variations in SOFA score and identify early predictors of short-term mortality in a cohort of patients with septic shock, treated with HCO-CVVHD for acute kidney injury (AKI). METHODS:An observational prospective multicenter cohort study was conducted in four mixed medical-surgical ICUs. Thirty-eight patients with septic shock and AKI (KDIGO stage?1) treated with HCO-CVVHD have been included in this study. Patients were divided into Survivors and non-Survivors according to mortality observed at 72nd hr of treatment. The variation of SOFA scores and clinical/biochemical parameters were described over time for the entire population and specifically for Survivors and non-Survivors. Similarly, circulating inflammatory mediators (as IL-6, TNF-a and IL-10) were described over time. A logistic regression analysis was used to identify the baseline clinical and biochemical parameters associated with 72 hrs-ICU mortality. RESULTS:Overall, the mean SOFA score was 12±3 at baseline, 10.9±3 at 6hrs, 9.8±3 at 12hrs, 8.9±3.3 at 24 hrs, and 8±3.5 at 48 hrs after HCO-CVVHD initiation; and 6.5±2.7 at 24 hrs and 6.6±3 at 48 hrs after HCO-CVVHD discontinuation. In the multivariate regression analysis, baseline serum lactate levels and AKI stage independently correlated with short-term mortality during HCO-CVVHD. A significant reduction was observed in circulating levels of TNF? and IL-6 among Survivors. CONCLUSIONS:SOFA score significantly decreased early after initiation of HCO-CVVHD in patients with septic AKI. Baseline lactate levels and the AKI stage resulted to be associated to 72 hrs-ICU-mortality.
Project description:Sepsis-related acute kidney injury (AKI) accounts for major morbidity and mortality among the critically ill. Heparin-binding protein (HBP) is a promising biomarker in predicting development and prognosis of severe sepsis and septic shock that has recently been proposed to be involved in the pathophysiology of AKI. The objective of this study was to investigate the added predictive value of measuring plasma HBP on admission to the intensive care unit (ICU) regarding the development of septic AKI.We included 601 patients with severe sepsis or septic shock from the prospective, observational FINNAKI study conducted in seventeen Finnish ICUs during a 5-month period (1 September 2011-1 February 2012). The main outcome measure was the development of KDIGO AKI stages 2-3 from 12 h after admission up to 5 days. Statistical analysis for the primary endpoint included construction of a clinical risk model, area under the receiver operating curve (ROC area), category-free net reclassification index (cfNRI) and integrated discrimination improvement (IDI) with 95% confidence intervals (95% CI).Out of 511 eligible patients, 101 (20%) reached the primary endpoint. The addition of plasma HBP to a clinical risk model significantly increased ROC area (0.82 vs. 0.78, p = 0.03) and risk classification scores: cfNRI 62.0% (95% CI 40.5-82.4%) and IDI 0.053 (95% CI 0.029-0.075).Plasma HBP adds predictive value to known clinical risk factors in septic AKI. Further studies are warranted to compare the predictive performance of plasma HBP to other novel AKI biomarkers.
Project description:High-density cholesterol (HDL-C) levels are influenced by genetic variation in several genes. Low levels of HDL-C have been associated with increased risk of acute kidney injury (AKI). We investigated whether genetic polymorphisms in ten genes known to regulate HDL-C levels are associated with both HDL-C levels and AKI development during sepsis. Two cohorts were retrospectively analyzed: Derivation Cohort (202 patients with sepsis enrolled at the Emergency Department from 2011 to 2014 in Vancouver, Canada); Validation Cohort (604 septic shock patients enrolled into the Vasopressin in Septic Shock Trial (VASST)). Associations between HDL-related genetic polymorphisms and both HDL-C levels, and risk for clinically significant sepsis-associated AKI (AKI KDIGO stages 2 and 3) were evaluated. In the Derivation Cohort, one genetic variant in the Cholesteryl Ester Transfer Protein (CETP) gene, rs1800777 (allele A), was strongly associated with lower HDL-C levels (17.4?mg/dL vs. 32.9?mg/dL, P?=?0.002), greater CETP mass (3.43?µg/mL vs. 1.32?µg/mL, P?=?0.034), and increased risk of clinically significant sepsis-associated AKI (OR: 8.28, p?=?0.013). Moreover, the same allele was a predictor of sepsis-associated AKI in the Validation Cohort (OR: 2.38, p?=?0.020). Our findings suggest that CETP modulates HDL-C levels in sepsis. CETP genotype may identify patients at high-risk of sepsis-associated AKI.
Project description:Acute kidney injury frequently complicates septic shock and independently predicts mortality in this population. Clinical factors alone do not entirely account for differences in risk of acute kidney injury between patients. Genetic variants are likely to explain this differential susceptibility. To identify genetic variants linked to acute kidney injury susceptibility, we conducted a high-density genotyping association study in a large population of patients with septic shock.Retrospective study.Tertiary academic medical center.One thousand two hundred and sixty-four patients with septic shock were analyzed to elucidate clinical risk factors associated with the development of acute kidney injury. Among them, 887 Caucasian patients were randomly split into discovery and validation cohorts and genotyped using the Illumina Human-CVD BeadChip (Illumina, San Diego, CA).None.Six hundred and twenty-seven of the 1,264 patients with septic shock and 441 of the 887 patients with genotyping data developed acute kidney injury within the first 72 hrs of intensive care unit admission. Five single nucleotide polymorphisms were associated with acute kidney injury in both the discovery and validation cohorts. Two of these were in the BCL2 gene and both were associated with a decreased risk of acute kidney injury (rs8094315: odds ratio 0.61, p = .0002; rs12457893: odds ratio 0.67, p = .0002, both for combined data). Bcl-2 is involved in the apoptosis pathway, which has previously been implicated in acute kidney injury. Another single nucleotide polymorphism was in the SERPINA4 gene, whose protein product, kallistatin, has been linked to apoptosis in the kidney.Large-scale genotyping reveals two single nucleotide polymorphisms in the BCL2 gene and a single nucleotide polymorphism in the SERPINA4 gene associated with a decreased risk of developing acute kidney injury, supporting the putative role of apoptosis in the pathogenesis of acute kidney injury.