Incidence, biomarkers, and outcome of acute kidney injury in critically ill adults

Acute kidney injury (AKI) is a syndrome encompassing kidney damage from mild injury to total loss of function that seriously disturbs the homeostasis of fluid and electrolyte balances. The objectives of this study were to evaluate the incidence, risk factors, and outcome of acute kidney injury in adult intensive care unit (ICU) patients in Finland, and to test the ability of two new biomarkers to predict AKI, renal replacement therapy (RRT), and 90-day mortality in ICU patients. A prospective, observational FINNAKI-study was conducted in 17 Finnish ICUs and all admitted patients were screened for eligibility during the study period of five months (2011-2012). All adult emergency admissions and elective admissions with an expected stay over 24 hours were included. AKI was defined with the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Study I included all patients in the FINNAKI study and evaluated the incidence and risk factors for AKI and reported the 90-day mortality of patients with AKI. Of the 2901 patients 1141 (39%) developed AKI during the screening period of five days. The proportions of patients in the different stages of AKI were 499 (17%) in stage 1, 232 (8%) in stage 2, and 410 (14%) in stage 3. RRT was initiated for 272 (9%) patients. The population-based incidence of AKI was 746 per million adults per year. Patients that developed AKI were older and more severely ill, and had more chronic comorbidities than patients without AKI. Hypovolaemia prior to ICU admission, administration of diuretics or colloids (HES or gelatin) prior to ICU admission, and chronic kidney disease were independent risk factors for AKI. Of the 1141 AKI patients, 385 (34%) died within 90-days. In study II urine neutrophil gelatinase-associated lipocalin (NGAL) was measured from 1042 patients. NGAL predicted AKI with an AUC (95% CI) of 0.733 (0.701 0.765), RRT with an AUC (95% CI) of 0.839 (0.797 0.880), and 90-day mortality with an AUC (95% CI) of 0.634 (0.593 0.675). In Study III urine interleukin-18 (IL-18) was analysed from 1439 patients. IL-18 predicted the development of AKI with an AUC (95%CI) of 0.586 (0.546 - 0.627), initiation of RRT with an AUC (95% CI) of 0.655 (0.572 - 0.739), and 90-day mortality with an AUC (95% CI) of 0.536 (0.497 - 0.574). Study IV included 1568 patients and evaluated the 6-month mortality and the survivors health-related quality of life (HRQol) at ICU admission and six-months later with the EQ-5D questionnaire. The EQ-5D index for AKI patients at six-months (0.676) was lower than for the age- and sex-matched general population (0.826) but equal to that of patients without AKI (0.690). There was no significant change in the EQ-5D over six-months for either patient group. Despite their measured lower HRQol, AKI patients evaluated their quality of life to be as good as that of the age- and sex-matched general population at six-months after the ICU treatment with the EQ-5D visual analogue scale. Of the 635 AKI patients in this study, 224 (35%) died within 6-months. Incidence of AKI among critically ill patients was high. Hypovolaemia, diuretics, and colloids prior to ICU admission were independently associated with the development of AKI. In this population, urine NGAL was statistically associated with the need to initiate RRT, but the transformation of this result into clinical practice is complicated. Urine NGAL lacks power to predict AKI or 90-day mortality. Urine IL-18 has no adequate power to predict AKI, RRT, or 90-Day mortality in critically ill adult patients. AKI was associated with significantly increased 90-day and 6-month mortality. The HRQol of all ICU patients was lower than that of the age- and sex-matched general population already before ICU treatment. This HRQol did not change during critical illness or during a six-month follow up. Despite their lower HRQol, AKI patients felt their health was equal to that of the general population.Akuutti munuaisvaurio (AKI) on monitekijäinen syndrooma, jonka taudinkuva vaihtelee lähes oireettomasta munuaisten täydelliseen toiminnanvajaukseen, mikä johtaa vakaviin ongelmiin elimistön neste- ja suolatasapainossa. AKI on yksi tehohoitopotilaiden yleisimmistä elinhäiriöistä, mutta sen esiintyvyyttä Suomessa ei ole kattavasti selvitetty. AKI:in ei ole spesifistä hoitoa ja siksi sen ennaltaehkäisy ja varhainen tunnistaminen on tärkeää. Käytössä olevien merkkiaineiden tilalle tarvittaisiin uusia ja parempia tehostamaan AKI:n varhaista tunnistamista. Tässä tutkimuksessa selvitettiin AKI:n esiintymistä tehohoitopotilailla Suomessa, AKI:lle altistavia tekijöitä sekä AKI:n vaikutusta potilaiden kuolleisuuteen sekä elämänlaatuun. Lisäksi tutkittiin kahden uuden merkkiaineen kykyä ennustaa AKI:n kehittymistä, munuaiskorvaushoidon (RRT) tarvetta ja kuolleisuutta. Tutkimusaineisto kerättiin valtakunnallisessa, etenevässä FINNAKI-tutkimuksessa viiden kuukauden aikana (2011-2012) 17 Suomalaisella teho-osastolla. Ensimmäisessä osatyössä tarkasteltiin AKI:n esiintymistä, riskitekijöitä sekä vaikutusta 3-kuukauden kuolleisuuteen 2901 potilaalla, joista 39% sai AKI:n. Potilaat, jota kehittivät AKI:n olivat vanhempia ja heillä oli enemmän perussairauksia. Lisäksi AKI potilaat olivat tehohoidon aikana vaikeammin sairaita kuin potilaat, jotka eivät saaneet AKI:a. Tutkimus kattoi alueellisesti 85% Suomen aikuisväestöstä ja tulosten mukaan miljoonaa aikuista kohden 746 saa tehohoitoisen AKI:n vuosittain. AKI potilaiden 3-kuukauden kuolleisuus oli kaksinkertainen (34%) verrattuna potilaisiin, jotka eivät saa AKI:a. Toisessa osatyössä arvioitiin virtsasta mitatun NGAL-proteiinin (neutrophil gelatinase-associated lipocalin) kykyä ennustaa AKI:n kehittymistä, RRT:n tarvetta ja 3-kuukauden kuolleisuutta 1042 potilaan aineistossa. NGAL ei riittävän hyvin ennustanut AKI:n kehittymistä eikä 3-kuukauden kuolleisuutta. NGAL:in kyky ennustaa RRT:tä oli tilastollisesti melko hyvä, mutta tämän tuloksen siirtäminen käytäntöön on monimutkaista, koska RRT:n aloittaminen ei useinkaan perustu selkeisiin kriteereihin vaan on hoitavan lääkärin päätös perustuen potilaan sen hetkiseen kokonaistilanteeseen. Kolmannessa osatyössä tutkittiin virtsasta mitatun IL-18-proteiinin (Interleukin 18) kykyä ennustaa AKI:a, RRT:n tarvetta ja 3-kuukauden kuolleisuutta 1439 potilaan aineistossa. IL-18 kyky ennustaa AKI:a, RRT:tä tai 3-kuukauden kuolleisuutta ei tässä aineistossa ollut riittävän hyvä kliiniseen käyttöön. Neljännessä osatyössä tarkasteltiin 1568 potilaan aineistossa AKI-potilaiden 6-kuukauden kuolleisuutta sekä AKI:n vaikutusta potilaiden elämänlaatuun. AKI-potilaiden 6-kuukauden kuolleisuus oli kaksinkertainen (35%) verrattuna muihin potilaisiin. Kaikkien potilaiden elämänlaatu oli tehohoitoa edeltävästi matalampi kuin normaaliväestön eikä se muuttunut 6-kuukauden seurannassa. AKI potilaat kuitenkin kokivat elämänlaatunsa olevan yhtä hyvä kuin muun väestön. Akuutti munuaisvaurio on hyvin yleinen tehohoitopotilailla ja lisää merkittävästi kuolleisuutta. Korkea ikä, perussairaudet sekä vaikea akuutti sairaus lisäävät riskiä saada AKI. Noin 4000 aikuista tehohoitopotilasta saa akuutin munuaisvaurion Suomessa vuosittain. Perustuen tämän tutkimuksen tuloksiin ja tänä vuonna julkaistuihin laskelmiin AKI:n yksinään aiheuttamasta lisäkuolleisuudesta (Vaara et al) ainakin noin 350 kuolemaa voitaisiin Suomessa vuosittain välttää, jos AKI:a ei esiintyisi. NGAL:n ja IL:18:sta ennustekykyä tutkittiin toistaiseksi laajimmissa tehohoitoaineistoissa. Tulokset osoittavat, ettei näiden merkkiaineiden kyky ennustaa AKI:a, RRT:tä tai kuolleisuutta ole riittävän hyvä kliiniseen käyttöön. Vaikka AKI merkittävästi lisää kuolleisuutta, ei sillä ole vaikutusta selvinneiden potilaiden elämänlaatuun. Kaikkien tehohoitopotilaiden elämänlaatu oli jo hoitoon tullessa matalampi verrattuna normaaliväestöön eikä tehohoidolla ollut vaikutusta siihen

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

The association of endothelial injury and systemic inflammation with perioperative myocardial infarction

Background Major surgery predisposes to endothelial glycocalyx injury. Endothelial glycocalyx injury associates with cardiac morbidity, including spontaneous myocardial infarction. However, the relation between endothelial glycocalyx injury and the development of perioperative myocardial infarction remains unknown. Methods Fifteen perioperative myocardial infarction patients and 60 propensity-matched controls were investigated in this prospective study. The diagnosis of perioperative myocardial infarction was based on repeated cardiac troponin T measurements, electrocardiographs and recordings of ischaemic signs and symptoms. We measured endothelial glycocalyx markers - soluble thrombomodulin, syndecan-1 and vascular adhesion protein 1 - and an inflammatory marker, namely interleukin-6, preoperatively and 6 h and 24 h postoperatively. We calculated the areas under the receiver operating characteristics curves (AUCs) to compare the performances of the different markers in predicting perioperative myocardial infarction. The highest value of each marker was used in the analysis. Results The interleukin-6 concentrations of perioperative myocardial infarction patients were significantly higher preoperatively and 6 and 24 h postoperatively (P = 0.002, P = 0.002 and P = 0.001, respectively). The AUCs (95% confidence intervals) for the detection of perioperative myocardial infarction were 0.51 (0.34-0.69) for soluble thrombomodulin, 0.63 (0.47-0.79) for syndecan-1, 0.54 (0.37-0.70) for vascular adhesion protein 1 and 0.69 (0.54-0.85) for interleukin-6. Conclusions Systemic inflammation, reflected by interleukin-6, associates with cardiac troponin T release and perioperative myocardial infarction. Circulating interleukin-6 demonstrated some potential to predict perioperative myocardial infarction, whereas endothelial glycocalyx markers did not.Peer reviewe

Urine NGAL as a biomarker for septic AKI : a critical appraisal of clinical utility-data from the observational FINNAKI study

Background: Neutrophil gelatinase-associated lipocalin (NGAL) is released from kidney tubular cells under stress as well as from neutrophils during inflammation. It has been suggested as a biomarker for acute kidney injury (AKI) in critically ill patients with sepsis. To evaluate clinical usefulness of urine NGAL (uNGAL), we post-hoc applied recently introduced statistical methods to a sub-cohort of septic patients from the prospective observational Finnish Acute Kidney Injury (FINNAKI) study. Accordingly, in 484 adult intensive care unit patients with sepsis by Sepsis-3 criteria, we calculated areas under the receiver operating characteristic curves (AUCs) for the first available uNGAL to assess discrimination for four outcomes: AKI defined by Kidney Disease: Improving Global Outcomes (KDIGO) criteria, severe (KDIGO 2-3) AKI, and renal replacement therapy (RRT) during the first 3 days of intensive care, and mortality at day 90. We constructed clinical prediction models for the outcomes and used risk assessment plots and decision curve analysis with predefined threshold probabilities to test whether adding uNGAL to the models improved reclassification or decision making in clinical practice. Results: Incidences of AKI, severe AKI, RRT, and mortality were 44.8% (217/484), 27.7% (134/484), 9.5% (46/484), and 28.1% (136/484). Corresponding AUCs for uNGAL were 0.690, 0.728, 0.769, and 0.600. Adding uNGAL to the clinical prediction models improved discrimination of AKI, severe AKI, and RRT. However, the net benefits for the new models were only 1.4% (severe AKI and RRT) to 2.5% (AKI), and the number of patients needed to be tested per one extra true-positive varied from 40 (AKI) to 74 (RRT) at the predefined threshold probabilities. Conclusions: The results of the recommended new statistical methods do not support the use of uNGAL in critically ill septic patients to predict AKI or clinical outcomes.Peer reviewe

Common Inflammation-Related Candidate Gene Variants and Acute Kidney Injury in 2647 Critically Ill Finnish Patients

Acute kidney injury (AKI) is a syndrome with high incidence among the critically ill. Because the clinical variables and currently used biomarkers have failed to predict the individual susceptibility to AKI, candidate gene variants for the trait have been studied. Studies about genetic predisposition to AKI have been mainly underpowered and of moderate quality. We report the association study of 27 genetic variants in a cohort of Finnish critically ill patients, focusing on the replication of associations detected with variants in genes related to inflammation, cell survival, or circulation. In this prospective, observational Finnish Acute Kidney Injury (FINNAKI) study, 2647 patients without chronic kidney disease were genotyped. We defined AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We compared severe AKI (Stages 2 and 3, n = 625) to controls (Stage 0, n = 1582). For genotyping we used iPLEX(TM) Assay (Agena Bioscience). We performed the association analyses with PLINK software, using an additive genetic model in logistic regression. Despite the numerous, although contradictory, studies about association between polymorphisms rs1800629 in TNFA and rs1800896 in IL10 and AKI, we found no association (odds ratios 1.06 (95% CI 0.89-1.28, p = 0.51) and 0.92 (95% CI 0.80-1.05, p = 0.20), respectively). Adjusting for confounders did not change the results. To conclude, we could not confirm the associations reported in previous studies in a cohort of critically ill patients.Peer reviewe

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