Urinary actin, as a potential marker of sepsis-related acute kidney injury: A pilot study

Abstract

Introduction A major complication of sepsis is the development of acute kidney injury (AKI). Recently, it was shown that intracellular actin released from damaged tissues appears in the urine of patients with multiple organ dysfunction syndrome. Our aims were to measure urinary actin (u-actin) concentrations of septic and control patients and to test if u-actin levels could predict AKI and mortality. Methods Blood and urine samples were collected from septic and sepsis-related AKI patients at three time points (T1-3): T1: within 24 hours after admission; T2: second day morning; T3: third day morning of follow-up. Patients with malignancies needing palliative care, end-stage renal disease or kidney transplantation were excluded. Serum and u-actin levels were determined by quantitative Western blot. Patients were categorized by the Sepsis-3 and KDIGO AKI classifications. Results In our study, 17 septic, 43 sepsis-induced AKI and 24 control patients were enrolled. U-actin levels were higher in septic patients compared with controls during follow-up (p<0.001). At T1, the septic and sepsis-related AKI groups also showed differences (p<0.001), yet this increase was not statistically significant at T2 and T3. We also detected significantly elevated u-actin concentrations in AKI-2 and AKI-3 septic patients compared with AKI-1 septic patients (p<0.05) at T1 and T3, along with a significant increase in AKI-2 septic patients compared with AKI-1 septic patients at T2 (p<0.01). This tendency remained the same when referring u-actin to urine creatinine. Parameters of first-day septic patient samples could discriminate AKI from non-AKI state (AUC ROC, p<0.001): u-actin: 0.876; se-creatinine: 0.875. Derived cut-off value for u-actin was 2.63 μg/L (sensitivity: 86.0%, specificity: 82.4%). Conclusion U-actin may be a complementary diagnostic biomarker to se-creatinine in sepsis-related AKI while higher u-actin levels also seem to reflect the severity of AKI. Further investigations may elucidate the importance of u-actin release in sepsis-related AKI.

Measurement of Urinary Gc-Globulin by a Fluorescence ELISA Technique: Method Validation and Clinical Evaluation in Septic Patients—A Pilot Study

“…We also tested the combined predictive value of u-Gc/u-creatinine, u-Cys-C/u-creatinine, u-ORM/u-creatinine and the gold standard se-creatinine and found a more robust diagnostic value for sepsis-associated AKI than in case of the individual markers. Our finding underlines the role of the multi-marker approach in AKI, which has already been proposed by several research groups [8,10].…”

“…For timely diagnosis, treatment and prediction of sepsis-associated AKI, biomarkers measured with rapid assays could be essential laboratory tools. Apart from the gold standard AKI functional marker, se-creatinine, several other markers have been investigated, including AKI stress markers (e.g., TIMP-2 [tissue inhibitor of metalloproteinase-2], IGFBP7 [insulin-like growth factor binding protein]), damage markers (e.g., NGAL, KIM-1 [kidney injury molecule 1]) and functional markers (e.g., Cystatin C, penKID [proenkephalin A 119-159]) with various success [8,10].…”

“…AKI criteria are fulfilled in case of a patient, when there is an increase in serum creatinine level by ≥0.3 mg/dL (≥26.5 µmol/L) within 48 h, or an increase in serum creatinine level to ≥1.5 times compared with baseline within the previous 7 days, or when urine volume decreases ≤0.5 mL/kg/h for 6 h. AKI itself is a heterogeneous syndrome leading to different clinical phenotypes because multiple mechanisms (e.g., inflammation, microcirculatory and mitochondrial dysfunction, nephrotoxic drugs) contribute to organ injury across the course of sepsis. Besides the clinical symptoms, there is still ongoing research for obtaining laboratory parameters as well, to aid diagnosis and to predict future complications with a special emphasis on AKI [9,10].…”

“…However, many other markers have been tested for the diagnosis and follow-up of sepsis such as presepsin, calprotectin, proinflammatory interleukins, monocyte chemoattractant protein-1, pentraxin-3, mid-regional fragment of pro-adrenomedullin and many others [13]. Trying to establish novel sepsis markers with a potential predictive value regarding organ dysfunctions as well, during the past few years, our research group has found non-commercially available complementary laboratory tests [10,[14][15][16][17][18][19][20][21][22] and adapted most of them to automated laboratory instrumentation including serum gelsolin (GSN), Gc-globulin (Gc), presepsin/GSN ratio, and urinary markers such as orosomucoid (u-ORM), Cystatin C (u-CysC) and neutrophil gelatinase associated lipocalin (u-NGAL).…”

“…In addition, high amount of free extracellular G-actin impairs DNase-1-mediated clearance of cell-free (cf) DNA, resulting in persistently elevated blood levels of cytotoxic cfDNA, which contributes to multiple organ dysfunction syndrome [27,28]. Excess actin in the plasma reduces the level of scavenger actin-binding proteins (GSN, Gc-globulin, thymosin beta-4), and excess actin can also be found in the urine of the patients who could have a diagnostic value regarding sepsis-related AKI [10,16,20,21,[29][30][31]. Serum Gc-globulin is a low molecular weight (52-59 kDa) glycosylated α2-globulin produced by the liver.…”