Urinary Biomarkers Indicative of Apoptosis and Acute Kidney Injury in the Critically Ill

BackgroundApoptosis is a key mechanism involved in ischemic acute kidney injury (AKI), but its role in septic AKI is controversial. Biomarkers indicative of apoptosis could potentially detect developing AKI prior to its clinical diagnosis.MethodsAs a part of the multicenter, observational FINNAKI study, we performed a pilot study among critically ill patients who developed AKI (n = 30) matched to critically ill patients without AKI (n = 30). We explored the urine and plasma levels of cytokeratin-18 neoepitope M30 (CK-18 M30), cell-free DNA, and heat shock protein 70 (HSP70) at intensive care unit (ICU) admission and 24h thereafter, before the clinical diagnosis of AKI defined by the Kidney Disease: Improving Global Outcomes - creatinine and urine output criteria. Furthermore, we performed a validation study in 197 consecutive patients in the FINNAKI cohort and analyzed the urine sample at ICU admission for CK-18 M30 levels.ResultsIn the pilot study, the urine or plasma levels of measured biomarkers at ICU admission, at 24h, or their maximum value did not differ significantly between AKI and non-AKI patients. Among 20 AKI patients without severe sepsis, the urine CK-18 M30 levels were significantly higher at 24h (median 116.0, IQR [32.3-233.0] U/L) than among those 20 patients who did not develop AKI (46.0 [0.0-54.0] U/L), P = 0.020. Neither urine cell-free DNA nor HSP70 levels significantly differed between AKI and non-AKI patients regardless of the presence of severe sepsis. In the validation study, urine CK-18 M30 level at ICU admission was not significantly higher among patients developing AKI compared to non-AKI patients regardless of the presence of severe sepsis or CKD.ConclusionsOur findings do not support that apoptosis detected with CK-18 M30 level would be useful in assessing the development of AKI in the critically ill. Urine HSP or cell-free DNA levels did not differ between AKI and non-AKI patients

Soluble CD73 in Critically Ill Septic Patients Data from the Prospective FINNAKI Study

Background CD73 dephosphorylates adenosine monophosphate to adenosine that is an anti-inflammatory molecule inhibiting immune activation and vascular leakage. Therefore, CD73 could be an interesting mediator both in sepsis and acute kidney injury (AKI). We aimed to explore the soluble CD73 (sCD73) levels and their evolution in critically ill patients with severe sepsis and, second, to scrutinize the potential association of sCD73 levels with AKI and 90-day mortality.Methods This was a post-hoc laboratory analysis of the prospective, observational FINNAKI study conducted in 17 Finnish ICU during 5 months in 2011-2012. Plasma samples of 588 patients admitted with severe sepsis/shock or with developing severe sepsis were analyzed at 0h (ICU admission) and 24h, and additionally, on day 3 or day 5 from a subset of the patients.Results The median [IQR] sCD73 levels at 0h were 5.11 [3.29-8.28] ng/mL and they decreased significantly from 0h to 4.14 [2.88-7.11] ng/mL at 24h, P<0.001. From 24h to Day 3 (n = 132) the sCD73 levels rose to 5.18 [2.98-8.83] ng/mL (P = 0.373) and from 24h to Day 5 (n = 224) to 5.52 [3.57-8.90] ng/mL (P<0.001). Patients with AKI had higher sCD73 values at 0h and at 24h compared to those without AKI. Non-survivors with severe sepsis, but not with septic shock, had higher CD73 levels at each time-point compared to survivors. After multivariable adjustments, sCD73 levels at 0h associated independently neither with the development of AKI nor 90-day mortality.Conclusions Compared to normal population, the sCD73 levels were generally low at 0h, showed a decrease to 24h, and later an increase by day 5. The sCD73 levels do not seem useful in predicting the development of AKI or 90-day mortality among patients with severe sepsis or shock

Restrictive fluid management versus usual care in acute kidney injury (REVERSE-AKI) : a pilot randomized controlled feasibility trial

Purpose We compared a restrictive fluid management strategy to usual care among critically ill patients with acute kidney injury (AKI) who had received initial fluid resuscitation. Methods This multicenter feasibility trial randomized 100 AKI patients 1:1 in seven ICUs in Europe and Australia. Restrictive fluid management included targeting negative or neutral daily fluid balance by minimizing fluid input and/or enhancing urine output with diuretics administered at the discretion of the clinician. Fluid boluses were administered as clinically indicated. The primary endpoint was cumulative fluid balance 72 h from randomization. Results Mean (SD) cumulative fluid balance at 72 h from randomization was - 1080 mL (2003 mL) in the restrictive fluid management arm and 61 mL (3131 mL) in the usual care arm, mean difference (95% CI) - 1148 mL (- 2200 to - 96) mL, P = 0.033. Median [IQR] duration of AKI was 2 [1-3] and 3 [2-7] days, respectively (median difference - 1.0 [- 3.0 to 0.0], P = 0.071). Altogether, 6 out of 46 (13%) patients in the restrictive fluid management arm and 15 out of 50 (30%) in the usual care arm received renal replacement therapy (RR 0.42; 95% CI 0.16-0.91), P = 0.043. Cumulative fluid balance at 24 h and 7 days was lower in the restrictive fluid management arm. The dose of diuretics was not different between the groups. Adverse events occurred more frequently in the usual care arm. Conclusions In critically ill patients with AKI, a restrictive fluid management regimen resulted in lower cumulative fluid balance and less adverse events compared to usual care. Larger trials of this intervention are justified.Peer reviewe

Association of endothelial and glycocalyx injury biomarkers with fluid administration, development of acute kidney injury, and 90-day mortality: data from the FINNAKI observational study

Background Injury to endothelium and glycocalyx predisposes to vascular leak, which may subsequently lead to increased fluid requirements and worse outcomes. In this post hoc study of the prospective multicenter observational Finnish Acute Kidney Injury (FINNAKI) cohort study conducted in 17 Finnish intensive care units, we studied the association of Syndecan-1 (SDC-1), Angiopoetin-2 (Ang-2), soluble thrombomodulin (sTM), vascular adhesion protein-1 (VAP-1) and interleukin-6 (IL-6) with fluid administration and balance among septic critical care patients and their association with development of acute kidney injury (AKI) and 90-day mortality. Results SDC-1, Ang-2, sTM, VAP-1 and IL-6 levels were measured at ICU admission from 619 patients with sepsis. VAP-1 decreased (p 12 h from ICU admission (AKI(>12 h)). They had higher sTM levels than patients without AKI, and after multivariable adjustment log, sTM level was associated with AKI(>12 h) with OR (95% CI) of 12.71 (2.96-54.67), p = 0.001). Ninety-day non-survivors (n = 180; 29.1%) had higher SDC-1 and sTM levels compared to survivors. After adjustment for known confounders, log SDC-1 (OR [95% CI] 2.13 [1.31-3.49], p = 0.002), log sTM (OR [95% CI] 7.35 [2.29-23.57], p < 0.001), and log Ang-2 (OR [95% CI] 2.47 [1.44-4.14], p = 0.001) associated with an increased risk for 90-day mortality. Finally, patients who had high levels of all three markers, namely, SDC-1, Ang-2 and sTM, had an adjusted OR of 5.61 (95% CI 2.67-11.79; p < 0.001) for 90-day mortality. Conclusions VAP-1 and IL-6 associated with fluid administration on the first ICU day. After adjusting for confounders, sTM was associated with development of AKI after 12 h from ICU admission. SDC-1, Ang-2 and sTM were independently associated with an increased risk for 90-day mortality

Effects of Fluids on the Macro- and Microcirculations.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2018. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2018. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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