Acute kidney injury in severe sepsis and septic shock

Severe sepsis is the main cause of acute kidney injury (AKI) among critically ill patients. Septic AKI has been shown to associate with lower mean arterial pressure (MAP) levels. The initiation of renal replacement therapy (RRT) is mainly based on clinical judgment. The objectives of this study were to assess the incidence and 90-day mortality of patients with severe sepsis associated AKI treated in the intensive care units (ICUs), to evaluate the impact of MAP on development of AKI, to assess the differences in proportion of use of RRT in patients with septic shock, and to develop predictive model for one-year mortality among ICU-treated patients with AKI. All patients were from the prospective, observational FINNAKI study conducted in 17 Finnish ICUs over the five-month study period in 2011-2012. AKI was defined by Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Of the 918 patients with severe sepsis, 488 had AKI (53%). Patients with septic AKI were older, had more comorbidities, and were more severely ill than patients without AKI. The 90-day mortality rate of the septic patients with AKI was higher (38%) compared to patients with severe sepsis without AKI (25%). The time-adjusted MAP during the first 24 hours in the ICU was lower in septic patients with development of AKI (74 mmHg) than in those septic patients without development of AKI (79 mmHg). The proportion of RRT-treated patients in patients with septic shock ranged from 3% to 35 % across Finnish ICUs. The variation in proportion of RRT among patients with septic shock between high- and low-RRT ICUs was explained by differences in case-mix and in severity of organ dysfunction. Indications for RRT or 90-day mortality did not differ between ICU groups. The one-year mortality among patients with AKI was 40%. Advanced age, number of co-morbidities, higher modified SAPS II score, mechanical ventilation and the lowest base excess value on the third day (D3), and the highest bilirubin value by D3 were predictors of one-year mortality. The severity of AKI, or the presence of severe sepsis, did not remain as predictors for one-year mortality. Conclusions: Over half of the patients with severe sepsis had AKI. Avoidance of time-adjusted MAP below 73mmHg may be beneficial for prevention of the progression of AKI in patients with severe sepsis. Despite 10-fold variation in proportion of RRT in patients with septic shock, the 90-day mortality of these patients was similar between high-RRT ICUs and low-RRT ICUs. The predictive model based on data by the third day in the ICU might be clinically useful in identifying patients with high risk for long-term mortality.Yleisin akuutin munuaisvaurion aiheuttaja kriittisesti sairailla potilailla on vaikea sepsis. Matala verenpaine lisää akuutin munuaisvaurion riskiä septisillä potilailla. Munuaiskorvaushoidon aloittaminen perustuu yleensä kliiniseen arvioon. Tutkimuksen tavoitteena oli selvittää vaikeaan sepsikseen liittyvän akuutin munuaisvaurion esiintyvyys Suomen teho-osastoilla sekä näiden potilaiden 90-vuorkokauden kuolleisuus; arvioida keskiverenpaineen vaikutusta munuaisvaurion kehittymiseen ja selvittää munuaiskorvaushoidon esiintyvyys septisillä shokkipotilailla. Lisäksi kehitettiin ennustemalli yhden vuoden kuolleisuudelle tehohoidossa oleville akuuttia munuaisvauriota sairastaville potilaille. Potilaat kuuluivat prospektiiviseen, havainnoivaan FINNAKI tutkimukseen, joka toteutettiin 17 suomalaisella teho-osastolla 5 kk aikana 2011-2012. Munuaisvaurio määriteltiin Kidney Disease: Improving Global Outcomes (KDIGO) kriteerien mukaisesti. Akuutti munuaisvaurio esiintyi 53% (488/918) vaikeaa sepsistä sairastavilla potilailla. Munuaisvaurion kehittäneet olivat iäkkäämpiä ja kroonisesti sekä akuutisti sairaampia. Akuuttia munuaisvauriota sairastavien potilaiden 90-vrk:n kuolleisuus (38%) oli korkeampi verrattuna sepsispotilaisiin ilman munuaisvauriota (25%). Keskiverenpaine oli matalampi akuutin munuaisvaurion kehittäneillä sepsispotilailla (74mmHg) verrattuna potilaisiin, joille munuaisvauriota ei kehittynyt (79 mmHg). Munuaiskorvaushoidettujen osuus septisistä shokkipotilaista vaihteli 3% - 35% suomalaisilla teho-osastoilla. Tämä vaihtelu selittyi eroilla potilasaineistossa ja elinhäiriöiden vaikeusasteessa. Korvaushoidon aloitusindikaatioissa ja 90-vuorokauden kuolleisuudessa ei ollut eroa teho-osastoryhmien välillä. Munuaisvauriopotilaiden yhden vuoden kuolleisuus oli 40%. Korkea ikä, kroonisten sairauksien lukumäärä, korkeat SAPS II pisteet, hengityskonehoito ja matalin emäsvajearvo kolmantena tehohoitopäivänä sekä korkein bilirubiinipitoisuus kolmanteen tehohoitopäivään mennessä ja olivat kuolemaa ennustavia tekijöitä. Munuaisvaurion vaikeusaste tai vaikea sepsis eivät ennustaneet yhden vuoden kuolleisuutta. Johtopäätökset: Yli puolet vaikeaa sepsistä sairastavista potilaista kehittivät akuutin munuaisvaurion. Matalan keskiverenpaineen (alle 73 mmHg) välttäminen voi ehkäistä munuaisvaurion kehittymistä. Munuaiskorvaushoidon esiintyvyyden erosta huolimatta septisten sokkipotilaiden kuolleisuudessa ei ollut eroa teho-osastoryhmien välillä. Kolmen ensimmäisen tehohoitopäivän tietoihin perustuva ennustemalli voi olla kliinisesti hyödyllinen ennustamaan yhden vuoden kuolleisuutta munuaisvauriopotilailla

Neutrophil activation in septic acute kidney injury : A post hoc analysis of the FINNAKI study

Background Inflammation, reflected by high plasma interleukin-6 concentration, is associated with acute kidney injury (AKI) in septic patients. Neutrophil activation has pathophysiological significance in experimental septic AKI. We hypothesized that neutrophil activation is associated with AKI in critically ill sepsis patients. Methods We measured plasma (n = 182) and urine (n = 118) activin A (a rapidly released cytosolic neutrophil protein), interleukin-8 (a chemotactic factor for neutrophils), myeloperoxidase (a neutrophil biomarker released in tissues), and interleukin-6 on intensive care unit admission (plasma and urine) and 24 hours later (plasma) in sepsis patients manifesting their first organ dysfunction between 24 hours preceding admission and the second calendar day in intensive care unit. AKI was defined by the Kidney Disease: Improving Global Outcomes criteria. Results Plasma admission interleukin-8 (240 [60-971] vs 50 [19-164] pg/mL, P <.001) and activin A (845 [554-1895] vs 469 [285-862] pg/mL, P <.001) were but myeloperoxidase (169 [111-300] vs 144 [88-215] ng/mL, P = .059) was not higher among patients with AKI compared with those without. Urine admission interleukin-8 (50.4 [19.8-145.3] vs 9.5 [2.7-28.7] ng/mL, P <.001) and myeloperoxidase (7.7 [1.5-12.6] vs 1.9 [0.4-6.9] ng/mL, P <.001) were but activin A (9.7 [1.4-42.6] vs 4.0 [0.0-33.0] ng/mL, P = .064) was not higher in AKI than non-AKI patients. Urine myeloperoxidase correlated with urine interleukin-8 (R = .627, P <.001) but not with plasma myeloperoxidase (R = .131, P = .158). Conclusion Interleukin-8 in plasma and urine was associated with septic AKI. Elevated plasma activin A indicates intravascular neutrophil activation in septic AKI. Concomitant plasma and urine myeloperoxidase measurements suggest neutrophil accumulation into injured kidneys.Peer reviewe

Two subphenotypes of septic acute kidney injury are associated with different 90-day mortality and renal recovery

Background The pathophysiology of septic acute kidney injury is inadequately understood. Recently, subphenotypes for sepsis and AKI have been derived. The objective of this study was to assess whether a combination of comorbidities, baseline clinical data, and biomarkers could classify meaningful subphenotypes in septic AKI with different outcomes. Methods We performed a post hoc analysis of the prospective Finnish Acute Kidney Injury (FINNAKI) study cohort. We included patients admitted with sepsis and acute kidney injury during the first 48 h from admission to intensive care (according to Kidney Disease Improving Global Outcome criteria). Primary outcomes were 90-day mortality and renal recovery on day 5. We performed latent class analysis using 30 variables obtained on admission to classify subphenotypes. Second, we used logistic regression to assess the association of derived subphenotypes with 90-day mortality and renal recovery on day 5. Results In total, 301 patients with septic acute kidney injury were included. Based on the latent class analysis, a two-class model was chosen. Subphenotype 1 was assigned to 133 patients (44%) and subphenotype 2 to 168 patients (56%). Increased levels of inflammatory and endothelial injury markers characterized subphenotype 2. At 90 days, 29% of patients in subphenotype 1 and 41% of patients in subphenotype 2 had died. Subphenotype 2 was associated with a lower probability of short-term renal recovery and increased 90-day mortality. Conclusions In this post hoc analysis, we identified two subphenotypes of septic acute kidney injury with different clinical outcomes. Future studies are warranted to validate the suggested subphenotypes of septic acute kidney injury.Peer reviewe

Burden of acute kidney injury and 90-day mortality in critically ill patients

Background Mortality rates associated with acute kidney injury (AKI) vary among critically ill patients. Outcomes are often not corrected for severity or duration of AKI. Our objective was to analyse whether a new variable, AKI burden, would outperform 1) presence of AKI, 2) highest AKI stage, or 3) AKI duration in predicting 90-day mortality. Methods Kidney Diseases: Improving Global Outcomes (KDIGO) criteria using creatinine, urine output and renal replacement therapy were used to diagnose AKI. AKI burden was defined as AKI stage multiplied with the number of days that each stage was present (maximum five), divided by the maximum possible score yielding a proportion. The AKI burden as a predictor of 90-day mortality was assessed in two independent cohorts (Finnish Acute Kidney Injury, FINNAKI and Simple Intensive Care Studies I, SICS-I) by comparing four multivariate logistic regression models that respectively incorporated either the presence of AKI, the highest AKI stage, the duration of AKI, or the AKI burden. Results In the FINNAKI cohort 1096 of 2809 patients (39%) had AKI and 90-day mortality of the cohort was 23%. Median AKI burden was 0.17 (IQR 0.07-0.50), 1.0 being the maximum. The model including AKI burden (area under the receiver operator curve (AUROC) 0.78, 0.76-0.80) outperformed the models using AKI presence (AUROC 0.77, 0.75-0.79, p = 0.026) or AKI severity (AUROC 0.77, 0.75-0.79, p = 0.012), but not AKI duration (AUROC 0.77, 0.75-0.79, p = 0.06). In the SICS-I, 603 of 1075 patients (56%) had AKI and 90-day mortality was 28%. Median AKI burden was 0.19 (IQR 0.08-0.46). The model using AKI burden performed better (AUROC 0.77, 0.74-0.80) than the models using AKI presence (AUROC 0.75, 0.71-0.78, p = 0.001), AKI severity (AUROC 0.76, 0.72-0.79. p = 0.008) or AKI duration (AUROC 0.76, 0.73-0.79, p = 0.009). Conclusion AKI burden, which appreciates both severity and duration of AKI, was superior to using only presence or the highest stage of AKI in predicting 90-day mortality. Using AKI burden or other more granular methods may be helpful in future epidemiological studies of AKI.Peer reviewe

Variation in the use of renal replacement therapy in patients with septic shock : a substudy of the prospective multicenter observational FINNAKI study

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Heme oxygenase-1 repeat polymorphism in septic acute kidney injury

Acute kidney injury (AKI) is a syndrome that frequently affects the critically ill. Recently, an increased number of dinucleotide repeats in the HMOX1 gene were reported to associate with development of AKI in cardiac surgery. We aimed to test the replicability of this finding in a Finnish cohort of critically ill septic patients. This multicenter study was part of the national FINNAKI study. We genotyped 300 patients with severe AKI (KDIGO 2 or 3) and 353 controls without AKI (KDIGO 0) for the guanine-thymine (GTn) repeat in the promoter region of the HMOX1 gene. The allele calling was based on the number of repeats, the cut off being 27 repeats in the S-L (short to long) classification, and 27 and 34 repeats for the S-M-L2 (short to medium to very long) classification. The plasma concentrations of heme oxygenase-1 (HO-1) enzyme were measured on admission. The allele distribution in our patients was similar to that published previously, with peaks at 23 and 30 repeats. The S-allele increases AKI risk. An adjusted OR was 1.30 for each S-allele in an additive genetic model (95% CI 1.01-1.66; p = 0.041). Alleles with a repeat number greater than 34 were significantly associated with lower HO-1 concentration (p<0.001). In septic patients, we report an association between a short repeat in HMOX1 and AKI risk

Early prolonged neutrophil activation in critically ill patients with sepsis

We hypothesised that plasma concentrations of biomarkers of neutrophil activation and pro-inflammatory cytokines differ according to the phase of rapidly evolving sepsis. In an observational study, we measured heparin-binding protein (HBP), myeloperoxidase (MPO), IL-6 and IL-8 in 167 sepsis patients on intensive care unit admission. We prospectively used the emergence of the first sepsis-associated organ dysfunction (OD) as a surrogate for the sepsis phase. Fifty-five patients (of 167, 33%) developed the first OD > 1 h before, 74 (44%) within +/- 1 h, and 38 (23%) > 1 h after intensive care unit admission. HBP and MPO were elevated at a median of 12 h before the first OD, remained high up to 24 h, and were not associated with sepsis phase. IL-6 and IL-8 rose and declined rapidly close to OD emergence. Elevation of neutrophil activation markers HBP and MPO was an early event in the evolution of sepsis, lasting beyond the subsidence of the pro-inflammatory cytokine reaction. Thus, as sepsis biomarkers, HBP and MPO were not as prone as IL-6 and IL-8 to the effect of sample timing.Peer reviewe

Heparin-binding protein (HBP) improves prediction of sepsis-related acute kidney injury

Background: 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. Methods: 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). Results: 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). Conclusions: 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.Peer reviewe