Inflammation and septic acute kidney injury

Acute kidney injury (AKI) is an everyday problem in intensive care: while in intensive care unit (ICU), up to 50% of critically ill adults are diagnosed with AKI. Additionally, fluid resuscitation may result in missed AKI cases due to dilution of creatinine (Cr) included in the Kidney Disease: Improving Global Outcomes (KDIGO) AKI criteria. Among the critically ill, the most common cause of AKI is sepsis. Sepsis and AKI combined, “septic AKI”, has particularly poor outcome. The mechanisms of septic AKI have been updated recently, highlighting inflammation as a potential target for therapeutic interventions. Urine neutrophil gelatinase-associated lipocalin (uNGAL), a neutrophil granule biomarker, has been suggested for AKI prediction and for prognostication of AKI evolution and outcome. The main study objectives were the following: 1) to determine if adjusting plasma Cr for fluid balance influences ICU AKI incidence (Study I), 2) to study the association of inflammatory and neutrophil activation biomarkers with septic AKI and to assess their temporal variations during early sepsis (Studies II–III), and 3) to scrutinize the incremental value of urine NGAL to predict septic AKI and other intensive care outcomes (Study IV). In Studies I–IV, we used clinical data and blood and urine samples prospectively collected for the FINNish Acute Kidney Injury (FINNAKI) study conducted in 17 Finnish ICUs. During a 6-month period, FINNAKI included all emergency admissions and elective admissions with an expected ICU stay >24 h. Study I included all FINNAKI patients without the following exclusion criteria: ICU stay <24 h, transfer to another ICU during the first five days, renal replacement therapy (RRT) before ICU admission, no weight or fluid input/output data available. We adjusted daily Cr values for cumulative fluid balance and applied either highest adjusted or highest unadjusted Cr alone or with urine output and RRT data to obtain AKI incidence, using the KDIGO criteria. Study I included 2044 patients. The mean difference between adjusted and unadjusted Cr values was 5 (±15) µmol/l. Using adjusted Cr together with urine output and RRT (full KDIGO criteria) yielded 19 (1%) additional AKI diagnoses, corresponding to 0.9% (95% confidence interval 0.3–1.6%) absolute difference in AKI incidence. Using only Cr criterium resulted in a slightly larger but not clinically meaningful difference. When we applied the full KDIGO criteria, no 90-day mortality differences existed between the reclassified and those not changing their AKI category. Thus, adjusting Cr for fluid balance was unnecessary to diagnose and stage AKI or to detect high–risk patients. Study II included 182 consecutive FINNAKI patients having both 0 h and 24 h plasma samples available and fulfilling severe sepsis criteria, by the American College of Chest Physicians and the Society of Critical Care Medicine, between 24 h preceding ICU admission and the second ICU day. We measured activin A, interleukins 6 (IL-6) and 8 (IL-8), and myeloperoxidase (MPO) from plasma and urine upon ICU admission and from plasma 24 h later and evaluated their associations with AKI. We found that increased plasma activin A and IL-8 were associated with septic AKI, indicating intravascular neutrophil activation in these patients. Concomitant plasma and urine MPO measurements suggested renal neutrophil accumulation in septic AKI. Study III included all Study II patients with a recorded time label for the first organ dysfunction. To assess the kinetics of heparin binding protein (HBP), MPO, IL-6, and IL-8 in early sepsis, we compared their plasma concentrations between 20 healthy controls and 167 sepsis patients divided into three groups: those having the plasma sample taken >1 h before organ dysfunction emergence, those with sample taken close to the first organ dysfunction emergence (±1 h), and those with sample taken >1 h after organ dysfunction emergence. All biomarkers were higher among sepsis patients than among controls. The short-lived IL-6 and IL-8 peaks occurred at the time of the first organ dysfunction, whereas HBP and MPO were already elevated before organ dysfunction and stayed high for at least 24 h following the onset of organ dysfunction. Study IV included all patients meeting the latest Sepsis-3 criteria from the previous FINNAKI-NGAL study. To evaluate the clinical applicability of uNGAL, we first constructed clinical risk models to predict AKI, RRT, and 90-day mortality using the routinely available admission data without uNGAL. We then assessed the ability of uNGAL to improve these risk models using new statistical instruments: risk assessment plot and decision curve analysis. Analyzing the 484 Study IV patients, we found that adding uNGAL to the clinical risk models led to modest improvement in AKI and RRT prediction, but no change in 90-day mortality prediction. According to test trade-offs between 40 (AKI) and 74 (RRT), uNGAL did not offer clinically meaningful incremental value to predict AKI or other relevant clinical outcomes.Äkillisesti sairastuneilla usein esiintyvän akuutin munuaisvaurion määritelmä perustuu kreatiniinin nousuun, virtsanerityksen vähenemiseen ja munuaiskorvaushoidon tarpeeseen. Teho-osastojen potilaista jopa 50 %:lla todetaan akuutti munuaisvaurio. Tehohoidossa akuutin munuaisvaurion tavallisin aiheuttaja on sepsis — yleistynyt infektio, johon liittyy henkeä uhkaavia elintoimintahäiriöitä. Sepsikseen liittyvän munuaisvaurion mekanismeja ei tunneta hyvin eikä ennaltaehkäisevää tai parantavaa hoitoa ole. Eläintutkimukset ovat tuoneet esiin tulehdusreaktion ja valkosolujen aktivaation merkityksen. Tutkimustietoa sepsispotilaista on kuitenkin vähän eikä kunnollista sepsiksen akuutin munuaisvaurion merkkiainetta ole kliinisessä käytössä. Tässä tutkimuksessa hyödynnettiin kansallisen FINNAKI-tutkimuksen tehohoitopotilasaineistoa veri- ja virtsanäytteineen. Ensin selvitettiin, vaikuttaako potilaan runsas nesteytys akuutin munuaisvaurion havaitsemiseen ja onko tällä merkitystä kuolleisuuteen. Toisessa ja kolmannessa osatyössä tutkittiin tulehduksen (interleukiinit 6 ja 8) ja neutrofiilisten valkosolujen aktivaation merkkiaineiden (aktiviini A, hepariinia sitova proteiini, myeloperoksidaasi) yhteyttä sepsispotilaiden munuaisvaurioon, sekä merkkiainenousun ajoittumista suhteessa elinvaurioiden ilmaantumiseen. Neljännessä osatyössä selvitettiin, auttaako neutrofiiligelatinaaseihin liittyvä lipokaliini (NGAL) sepsispotilaiden akuutin munuaisvaurion, munuaiskorvaushoidon ja kuolleisuuden ennustamisessa. Kreatiniinin suhteuttaminen nestetasapainoon ei vaikuttanut merkittävästi akuutin munuaisvaurion esiintyvyyteen. Sen seurauksena luokkaa vaihtaneiden (munuaisvaurio ↔ ei munuaisvauriota) kuolleisuudessa ei todettu eroa, jos akuutin munuaisvaurion kriteerinä käytettiin myös virtsaneritystä. Tulehdus- ja valkosoluaktivaation merkkiaineet assosioituivat sepsispotilaiden munuaisvaurioon. Samanaikaiset plasman ja virtsan myeloperoksidaasimittaukset viittasivat aktivoituneiden neutrofiilisten valkosolujen kerääntymiseen munuaisiin. Plasman tulehdusmerkkiaineiden (interleukiinit 6 ja 8) nopea nousu ja lasku ajoittui sepsiksessä lähelle ensimmäisen elintoimintahäiriön ilmaantumista. Neutrofiilisten valkosolujen aktivaation merkkiaineet hepariinia sitova proteiini ja myeloperoksidaasi olivat koholla jo ennen ensimmäisen elintoimintahäiriön ilmaantumista ja pysyivät korkeina kauemmin kuin interleukiinit 6 ja 8. Virtsan NGAL ei tuonut lisäapua sepsispotilaiden akuutin munuaisvaurion, munuaiskorvaushoidon tai kuolleisuuden ennustamiseen verrattuna rutiinilaboratoriokokeista ja kliinisestä arviosta saatuun tietoon

Fluid balance-adjusted creatinine in diagnosing acute kidney injury in the critically ill

Background Acute kidney injury (AKI) is often diagnosed based on plasma creatinine (Cr) only. Adjustment of Cr for cumulative fluid balance due to potential dilution of Cr and subsequently missed Cr-based diagnosis of AKI has been suggested, albeit the physiological rationale for these adjustments is questionable. Furthermore, whether these adjustments lead to a different incidence of AKI when used in conjunction with urine output (UO) criteria is unknown. Methods This was a post hoc analysis of the Finnish Acute Kidney Injury study. Hourly UO and daily plasma Cr were measured during the first 5 days of intensive care unit admission. Cr values were adjusted following the previously used formula and combined with the UO criteria. Resulting incidences and mortality rates were compared with the results based on unadjusted values. Results In total, 2044 critically ill patients were analyzed. The mean difference between the adjusted and unadjusted Cr of all 7279 observations was 5 (+/- 15) mu mol/L. Using adjusted Cr in combination with UO and renal replacement therapy criteria resulted in the diagnosis of 19 (1%) additional AKI patients. The absolute difference in the incidence was 0.9% (95% confidence interval [CI]: 0.3%-1.6%). Mortality rates were not significantly different between the reclassified AKI patients using the full set of Kidney Disease: Improving Global Outcomes criteria. Conclusion Fluid balance-adjusted Cr resulted in little change in AKI incidence, and only minor differences in mortality between patients who changed category after adjustment and those who did not. Using adjusted Cr values to diagnose AKI does not seem worthwhile in critically ill patients.Peer reviewe

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

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

Att vara förälder till ett barn som missbrukar

Den här kvalitativa studien undersöker hur det är att vara förälder till ett barn som missbrukar samt hur vardagslivet och hur relationer inom familjen samt till omgivningen påverkas. Studien utgår från en hermeneutisk forskningstradition med kvalitativ inriktning. Undersökningen bygger på fyra semistrukturerade intervjuer varav alla intervjupersoner har haft minst ett barn med missbruksproblem. Familjen är ett  mänskligt system, därför tolkas resultatet utifrån systemteorin. Resultatet visar att familjens vardag förändrades då de fick utstå påfrestningar av missbruket vilket ledde till att familjerelationerna försämrades. Undersökningen visar hur sorgen hos föräldrarna övergick till skuld och skam vilket resulterade i att familjen isolerade sig från omvärlden. Föräldrarna isolerade sig på grund av skammen men även för att man kände att samhället stämplade dem för att vara dåliga föräldrar. En slutsats är att föräldrar behöver stöd när ett barn i familjen missbrukar för att kunna hjälpa sitt barn samt själva få hjälp då många föräldrar utvecklat ett medberoendebeteende

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

Habitual FODMAP Intake in Relation to Symptom Severity and Pattern in Patients with Irritable Bowel Syndrome

Restricting intake of FODMAPs (Fermentable Oligo-, Di-, Monosaccharides and Polyols) is used as treatment for irritable bowel syndrome (IBS). However, whether habitual FODMAP consumption correlates to symptom severity, and if this relationship differs among IBS subtypes, is unclear. The aim was to study the relationship between habitual FODMAP intake and symptom severity. A total of 189 patients with IBS&mdash;IBS with constipation (IBS-C) n = 44 (22.3%), IBS with diarrhea (IBS-D) n = 54 (27.4%), mixed IBS (IBS-M) n = 46 (23.4%) and unsubtyped IBS (IBS-U) n = 46 (23.4%)&mdash;recorded food intake during four days. Symptom severity was measured with the IBS severity scoring system (IBS-SSS). For FODMAP intake, a lower lactose intake was noted among women with IBS-D, p = 0.009. In women, there was a statistically significant relationship between energy-adjusted FODMAP intake and IBS-SSS (r = 0.21, p = 0.003). This was mainly driven by the subtype IBS-U, where excess fructose intake accounted for 19.9% of explained variance in IBS-SSS (p = 0.007). This study demonstrates small differences in FODMAP intake among IBS patients with different subtypes. Association between IBS symptoms and FODMAP intake was most prominent in unsubtyped IBS. However, patients who are intolerant to certain FODMAPs may already have reduced their FODMAP intake, and this warrants future cohort or experimental studies to uncover

A Bayesian reanalysis of the Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial

Background Timing of initiation of kidney-replacement therapy (KRT) in critically ill patients remains controversial. The Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial compared two strategies of KRT initiation (accelerated versus standard) in critically ill patients with acute kidney injury and found neutral results for 90-day all-cause mortality. Probabilistic exploration of the trial endpoints may enable greater understanding of the trial findings. We aimed to perform a reanalysis using a Bayesian framework. Methods We performed a secondary analysis of all 2927 patients randomized in multi-national STARRT-AKI trial, performed at 168 centers in 15 countries. The primary endpoint, 90-day all-cause mortality, was evaluated using hierarchical Bayesian logistic regression. A spectrum of priors includes optimistic, neutral, and pessimistic priors, along with priors informed from earlier clinical trials. Secondary endpoints (KRT-free days and hospital-free days) were assessed using zero–one inflated beta regression. Results The posterior probability of benefit comparing an accelerated versus a standard KRT initiation strategy for the primary endpoint suggested no important difference, regardless of the prior used (absolute difference of 0.13% [95% credible interval [CrI] − 3.30%; 3.40%], − 0.39% [95% CrI − 3.46%; 3.00%], and 0.64% [95% CrI − 2.53%; 3.88%] for neutral, optimistic, and pessimistic priors, respectively). There was a very low probability that the effect size was equal or larger than a consensus-defined minimal clinically important difference. Patients allocated to the accelerated strategy had a lower number of KRT-free days (median absolute difference of − 3.55 days [95% CrI − 6.38; − 0.48]), with a probability that the accelerated strategy was associated with more KRT-free days of 0.008. Hospital-free days were similar between strategies, with the accelerated strategy having a median absolute difference of 0.48 more hospital-free days (95% CrI − 1.87; 2.72) compared with the standard strategy and the probability that the accelerated strategy had more hospital-free days was 0.66. Conclusions In a Bayesian reanalysis of the STARRT-AKI trial, we found very low probability that an accelerated strategy has clinically important benefits compared with the standard strategy. Patients receiving the accelerated strategy probably have fewer days alive and KRT-free. These findings do not support the adoption of an accelerated strategy of KRT initiation

Regional Practice Variation and Outcomes in the Standard Versus Accelerated Initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) Trial: A Post Hoc Secondary Analysis.

ObjectivesAmong patients with severe acute kidney injury (AKI) admitted to the ICU in high-income countries, regional practice variations for fluid balance (FB) management, timing, and choice of renal replacement therapy (RRT) modality may be significant.DesignSecondary post hoc analysis of the STandard vs. Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial (ClinicalTrials.gov number NCT02568722).SettingOne hundred-fifty-three ICUs in 13 countries.PatientsAltogether 2693 critically ill patients with AKI, of whom 994 were North American, 1143 European, and 556 from Australia and New Zealand (ANZ).InterventionsNone.Measurements and main resultsTotal mean FB to a maximum of 14 days was +7199 mL in North America, +5641 mL in Europe, and +2211 mL in ANZ (p p p p p p p p = 0.007).ConclusionsAmong STARRT-AKI trial centers, significant regional practice variation exists regarding FB, timing of initiation of RRT, and initial use of continuous RRT. After adjustment, such practice variation was associated with lower ICU and hospital stay and 90-day mortality among ANZ patients compared with other regions