Summary of the published studies in early urine and plasma biomarkers for detecting SA-AKI.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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Sepsis is a condition with life-threatening organ dysfunction caused by a dysregulated host response to systemic infection [1]. Sepsis is the leading cause of acute kidney injury (AKI) in critically ill patients especially in the intensive care unit (ICU). The morbidity and mortality of patients with sepsis-associated AKI (SA-AKI) is still high despite an advance in supportive care [2, 3]. Therefore, a well understanding of SA-AKI is essential not only for nephrologists but also for all physicians to enhance awareness and proper initiation of managements. In this chapter, we discuss several topics in SA-AKI, including the potential new therapeutic managements.
\nBecause SA-AKI definition follows the definition of AKI, in general, the understanding in AKI definition is necessary. Despite the heterogeneity in AKI definition with more than 35 equivalent terms within the last few decades [4], RIFLE (Risk, Injury, Failure, Loss of kidney function, End-stage kidney disease) and AKIN (Acute Kidney Injury Network) classification systems, published in 2004 and 2007, respectively, are widely accepted [5]. RIFLE classification stratifies AKI according to AKI severity as determined by serum creatinine (SCr) or glomerular filtration rate (GFR) and urine output (UO) into three categories; Risk (R), Injury (I), and Failure (F). In addition, RIFLE criteria also categorize advanced AKI into other two categories based on the duration of AKI, kidney function loss (L, persistent AKI > 4 weeks), and end-stage kidney disease (E, AKI > 3 months) [5]. In RIFLE classification, worsening of SCr must be over a 7-day period and persists for at least 24 h. In case of unknown data on previous SCr level, a baseline GFR between 75 and 100 ml/min/1.73 m2 is assumed, and the modification of diet in renal disease (MDRD) equation is recommended for an estimation of baseline renal function. However, the poor prediction of clinical outcomes from renal function derived by MDRD equation is demonstrated [6]. Therefore, RIFLE and AKIN classifications are modified [7]. In modified AKIN classification, the diagnostic accuracy is improved by precluding either SCr or GFR which discards the requirement of baseline SCr for AKI classification. Despite the improved diagnostic sensitivity of AKIN in comparison with RIFLE classification, AKI outcomes are not in consideration of AKIN system [8]. And AKIN does not synergize with RIFLE criteria in predicting in-hospital mortality of patients with critical illness. Recently, the kidney disease improving global outcomes (KDIGO) work group merges the RIFLE and AKIN classifications in order to establish one AKI classification [9]. KDIGO system defines AKI as an increase in SCr ≥0.3 mg/dL within 48 h or an increase in SCr to ≥1.5 times of baseline SCr or a urine volume of <0.5 mL/kg/h for 6 h. Baseline SCr is the known or presumed value that has occurred within the previous 7 days. In addition, AKI staging of KDIGO follows the AKIN classification with a simplification. KDIGO system shows some advantages over the RIFLE and AKIN classifications in AKI identification and AKI-outcomes prediction. Moreover, KDIGO introduces a new term of “acute kidney disease, AKD” which means the slower increase in SCr or GFR, >7 days but <3 months. This is because renal injury in some conditions progresses slowly and does not match with AKI definition where significant renal function declines within 7 days after the insults.
\nRegarding SA-AKI classification, Pereira et al. [10] demonstrate that SA-AKI with all of these three classifications—RIFLE, AKIN, and KDIGO—shows similar prediction ability (assessed by the area under the receiver operating characteristic (AUROC) curve) for in-hospital mortality (RIFLE 0.652, p < 0.001; AKIN 0.686, p < 0.001; KDIGO 0.658, p < 0.001). However, the study shows that RIFLE and KDIGO classifications identify AKI more than AKIN criteria. Thus, SA-AKI is AKI induced or enhanced by sepsis which could be classified with any of these three classification systems. It is also interesting to note that SA-AKI is another entity that should be separated from nephrotoxic and ischemic causes of AKI. In fact, inflammatory responses in SA-AKI seem to be more prominent than ischemic and nephrotoxic AKI [11].
\nA longitudinal, 10 years, cohort with more than 20 ICUs and almost 90,000 patients demonstrates the increased incidence of AKI by 2.8% per year [12]. In parallel, the incidence of sepsis and septic shock is on the rise. In the United States, the retrospective data from 22 years of hospital records reveal 8.7% annual increase in diagnosis of sepsis [13]. Sepsis is the most common contributing factor for AKI. The incidence of SA-AKI is 10–45% based on etiology and population [14, 15]. In surgical condition, the incidence may be as high as 60–70% [16], especially in the ICU setting (>50%) [3]. The severity of SA-AKI also depends on the underlying diseases as well as causes of sepsis [17].
\nPopulations with a high risk of SA-AKI are elderly patients, female gender, and medical comorbidities, including diabetes mellitus, chronic kidney disease (CKD), congestive heart failure, advanced liver disease, and malignancy [18, 19]. In addition, the source of infection and side effect of treatment also contribute as risk factors of SA-AKI. As such, intra-abdominal infection, urological sepsis, infective endocarditis, and blood stream infection are conditions that are susceptible to SA-AKI.
\nSepsis immune responses are very complex and possibly different among diverse etiologies. The progression of sepsis definition is parallel to the current understanding of sepsis pathophysiology in each period (\nFigure 1\n).
\nSummary of sepsis definition or main mechanisms in each period.
Indeed, the importance of hyperinflammation as a major component of sepsis is gradually altered by the progression in the understanding of sepsis-induced hypoinflammatory responses. The updated definition of sepsis focuses on organ dysfunction, host responses, and infection as an etiology [1]. This is due to the recognition that sepsis in the individual patient is different due to host factors (underlying disease, genetic susceptibility, duration of infection, and organ involvement) and organism factors (virulence and antibiotic susceptibility). Hence, the major mechanisms responsible for sepsis and the proper therapeutic strategies to encounter sepsis for each patient might be different. Indeed, several responsible molecular pathways of sepsis-induced hyperinflammatory response have been demonstrated (e.g., Toll-like receptor 4, Toll-like receptor 9, HMGB1, NF-κB, etc.) mostly in animal models with very rapid clinical progression [20]. These sepsis models enlighten us that the harness of innate immune responses in several processes with adequate organism control attenuates sepsis severity [21–29]. However, the control of innate immune-induced hyperinflammation results in only 50% survival. This demonstrates that other mechanisms might also contribute to the severity of sepsis. Indeed, the clinical observation from patients with sepsis demonstrates immunosuppression in sepsis as determined by (i) high susceptibility to secondary infection, (ii) defect in delayed-type hypersensitivity responses, and (iii) reactivation of dormant virus (e.g., herpes group) [30]. From these clinical observations, immunosuppressive phase of sepsis seems to occur at the late phase. However, Hotchkiss et al. nicely demonstrate the importance of sepsis-induced immune suppression and conclude that moribund stage of patients with sepsis could occur shortly after the onset of sepsis (either hyperimmune or hyporesponsive phase) [30].
\nAs such, the rapid immune exhaustion after sepsis has been demonstrated in mice with the defect of immune inhibition (Fc gamma receptor IIb-deficient mice) [31]. These mice lack the inhibitory signaling with prominent immune responses to infection. The preconditioning with endotoxin induces immune exhaustion and blunt responses of subsequent infection. In translational aspect, this is an example of the rapid immune-suppressive phase that occurs shortly after the onset of sepsis due to the preconditioning in the susceptible host. Moreover, bacterial sepsis also enhances the susceptibility to secondary fungal infection [32]. Interestingly, Candida albicans intravenous injection alone and with sepsis causes candidemia after injection at 7 days and 6 h, respectively. Sepsis induces candidemia approximately 1 week faster than non-sepsis control group. This model is also demonstrated that immunosuppression after sepsis could be very rapid, and the host factors are important for the direction of immune responses.
\nIn animal model, sepsis in the pre-conditioning models, pre-existing AKI or CKD or lupus manifestation, demonstrates the more severe hyperimmune responses as shown by the prominent cytokine storms [23, 26, 31, 33]. Then, the host factor is very important for inducing rapid progression due to hyper- or hypoimmune responses in sepsis. While several therapeutic strategies from animal studies are available mostly for controlling hyperimmune responsiveness, the clinical study in sepsis categorizes patients according to the severity of sepsis but not by the characteristic of immune response. Therefore, it is not surprising that nearly all of the clinical studies fail and the difference between animal models versus patients is blamed for the translational failure. The mechanistic-oriented approach with patient characterization by molecular biomarkers, but not simply with sepsis severity, should be more appropriate. Biomarkers for differentiating the direction of sepsis immune response are urgently needed. The anti-inflammatory treatment should be appropriate for patients in hyperimmune response phase and vice versa for immunosuppression phage. Moreover, hyper- and hypoimmune response in sepsis is dynamic and the monitoring biomarkers are necessary.
\nIn addition, the molecular-oriented treatment is also an interesting topic in sepsis. For example, anti-HMGB1 should be beneficial in sepsis condition with high HMGB1, and anti-TLR-4 should be appropriate for patients with increased TLR-4 expression on immune cells. Due to the possibility of heterogeneity pathways of sepsis immune responses, the tailor-made or individualized therapy might be the most suitable management of sepsis. However, the understanding in sepsis immune responses is still incomplete. Then, the current sepsis definition depending on sepsis-induced end-organ damage regardless of mechanistic responses is still fragmentary. More studies are needed to reach “sepsis mechanistic approach” in the future.
\nCurrently, the pathophysiology of SA-AKI is not completely known. Probably renal biopsy is rarely performed in SA-AKI. Hence, the basic knowledge of SA-AKI is based upon animal models which might be relevant only to a specific condition of SA-AKI in human [34]. For an example, AKI from cecal ligation and puncture model might be relevant to intra-abdominal sepsis but less appropriate representative of pneumonia-induced AKI. The interpretation and results translation from bench to bedside should be properly matched between models and sepsis conditions in patients. Hence, the experiments on the larger animals are performed but, unfortunately, the models might not represent all aspects of patient conditions. With the data gathering from patients and animal studies, the pathophysiology of SA-AKI is, at least in part, through overt inflammatory process-induced renal injury, tubular tight junction (TJ) injury, cell cycle arrest, cellular adaptation/apoptosis, and so on [35]. Perhaps, an alteration in microvascular oxygen transport during sepsis might be the major pathophysiology of SA-AKI. Here, we summarized the mechanisms of SA-AKI mentioned in the literatures (\nFigure 2\n).
\nImmune responses in sepsis. Due to renal microcirculation dysfunction (glomerular and tubular capillary), sepsis induces chemotaxis of inflammatory cells and proinflammatory responses leading to endothelial injury (a). Vascular permeability increases due to the downregulation of endothelial nitric oxide synthase (eNOS) activity and induction of inducible nitric oxide synthase (iNOS) (b). In parallel, inflammatory responses increase tissue factor and induce the coagulation system as demonstrated by microvascular thrombosis (c). In addition, inflammatory responses induce tubular cell injury, activate cell cycle arrest at G1 phase and cell apoptosis (d). The insufficient cell energy induces the abnormality in fusion/fission mechanisms of mitochondria resulting in mitochondrial injury (e). The toxic cell environment induced predominant mitochondria fission and dysfunction mitochondria (gray circle). The successful or failure of mitophagy activates cell regeneration or cell apoptosis, respectively (e, lower part).
The renal microcirculation is an important delivery system of blood and oxygen to kidney tissue. Decreased glomerular perfusion pressure in sepsis is due to microdynamic disturbance with approximately normal renal blood flow (RBF) [36]. However, reduced RBF in sepsis could be found only in some patients with the failure of cardiac output. In fact, sepsis induces hyper-dynamic cardiac responses with relatively high cardiac output. Although RBF is maintained or increased in sepsis, glomerular capillary hydrostatic pressure is insufficient to permit effective filtration because of efferent-afferent arteriolar imbalance function. Reduced GFR in persistent AKI is a result of several mechanisms including inappropriate activation of tubuloglomerular feedback (TG feedback) [37], tubular back-leak [38], tubular stasis/obstruction, nephrosarca, and altered glomerular permeability.
\nNormally, TG feedback is controlled by the concentration of chloride delivery to the distal nephron for the induction of afferent arteriole vasoconstriction. Its role is important to limit the hyperfiltration in case of high glomerular perfusion pressure. In SA-AKI, TG feedback is inappropriate due to high chloride presentation at distal nephron because of decreased chloride reabsorption at the proximal renal tubule. This results in overt afferent arteriole vasoconstriction. Marked arteriole vasoconstriction in combination with systemic hypotension causes profound decline in GFR [37].
\nTubular cell tight junction disturbance (tubular back-leak) is in the leak-back of non-selective ultrafiltration and ions from renal luminal site into basolateral portion. In SA-AKI, TJ is one of the target actions of endotoxin. Eadon et al. demonstrates direct structural damage of LPS at TJ. The injury of TJ, as determined by the injury at zonula occludens-1 (ZO-1) and claudins, is too severe to explain with LPS-induced-hemodynamic disturbance alone [38]. The tubular back-leak from TJ damage reduces UO by (i) reduced urine volume due to the leaking back of urine into circulation, (ii) increasing intra-renal pressure (renal intracapsular pressure or nephrosarca) [39], and (iii) cell debris-induced tubular lumen obstruction, tubular TJ damage, and abnormal TG feedback mechanisms. The reduction of GFR in SA-AKI also associates with altered glomerular permeability due to inflammation and endotoxins-induced direct glomerular endothelium damage [40, 41]. Nevertheless, the exact mechanisms of glomerular endothelium injury in human remain unknown.
\nAdditionally, an alteration of renal microcirculation might be a physiologic mechanism that aims to limit oxygen and nutrition of organisms. Melican et al. [42] demonstrated, in a urosepsis model, that renal ischemia facilitates bacterial isolation and defends against organisms in sepsis. The suppression of intravascular coagulation by heparin causes fatal urosepsis despite improved microvascular architectures.
\nRenal endothelial cells and its function play a central role in microcirculatory dysfunction during sepsis. Sepsis-induced systemic inflammatory cytokines activate endothelium cells and initiate the inflammatory process [41]. Moreover, sepsis induces hypercoagulable state in vessels at both micro- and macroscopic levels. In animal SA-AKI model, Drake et al. demonstrates an increased expression of tissue factor by glomerular endothelial cells in Escherichia coli sepsis [43]. The hypercoagulable state in SA-AKI also contributes to localized ischemia and hypoxia in the related intravascular thrombosis area, even though GFR is preserved [42].
\nEndothelial nitric oxide (NO) synthase (eNOS) induces NO which inhibits platelet aggregation and leukocyte activation. During sepsis, there is depletion of eNOS and activation of inducible NO synthase (iNOS). While eNOS has been shown to attenuate tissue ischemia, iNOS released from activated leukocytes and vascular smooth muscle cells causes vascular dysfunction [44, 45]. Langenberg et al. has recently demonstrated that NOS isoforms increase significantly in SA-AKI, particularly in renal cortex more than in medulla [46]. This may potentially lead to medullary ischemia due to intrarenal shunting.
\nMitochondria are organelles found in every cell and are very prominent in cells of energetic organs including kidney. They are known as the powerhouses of cells. Renal mitochondria are most densely concentrated due to the high and constant demand for adenosine triphosphate. Indeed, lack of cell energy and mitochondrial injury is demonstrated in several organs in sepsis [47]. Normally, mitochondrial dynamics is described as characteristics of “fission”and “fusion.”The mitochondrial fission, a cleavage of the defective parts of a mitochondrion, may be important for the maintenance of healthy organelles and necessary for mitochondria distribution to daughter cells during cell division. On the other hand, mitochondrial fusion is the multiple steps fusion between adjacent mitochondria to improve their functions. Both mitochondrial fission and fusion facilitate inter-mitochondria exchanges of metabolites and substrates to maintain the optimal functions that are essential to cell viability [48].
\nAutophagy is a cellular process by which cytoplasmic organelles are sequestered and delivered to lysosomes for the proper degradation. Therefore, it plays a crucial role in intracellular nutrient turnover, cell differentiation, cellular homeostasis, and viability [49]. But the overactivity of autophagy, however, may cause cell injury or death. In mouse models of SA-AKI, autophagy is rapidly induced and plays important roles in renoprotection [50]. Because mitochondria are prokaryote inhabited inside eukaryotic cell in symbiosis relationship, the breakdown of mitochondria will release several prokaryotic molecules that are capable of inflammatory activation as other pathogen-associated molecular patterns (PAMPs). Hence, the autophagy on mitochondria, as referred to mitophagy, protects unnecessary inflammatory responses and recycles nutrients from the injured mitochondria. In the same line with apoptosis, autophagy is the process that requires enough cell energy. In the condition with the excess injured-mitochondria for autophagy, some mitochondria rupture and mitochondrial cytochrome C further activate cell apoptosis. As such, if there are too many apoptotic bodies to clear by phagocytic cells, apoptotic cells will progress into secondary necrosis where the rupture of its membrane induces prominent inflammation. Hence, mitophagy is also postulated to be another cytoprotective process to control cellular metabolism through the balance in number of mitochondria. Mitophagy is linked to mitochondrial dynamics—fission and fusion—through the surveillance and clearance mechanisms [51].
\nTaken together, it is conceivable that during the early phase of SA-AKI, mitophagy is increased to control and clear the damaged mitochondria. However, as sepsis progress, the autophagy may be overwhelmed by injured mitochondria, and/or the autophagic processes are disrupted, leads to the abnormal cell functions. Therefore, well homeostasis of intracellular mitochondria to restore healthy mitochondrial mass may be essential for renoprotection and the recovery of renal function in SA-AKI.
\nCell cycle arrest is a protective mechanism to avoid entering the cell cycle during injury [52], thereby temporarily arresting cell cycle at G1 stage for reducing cell damage. In cecal ligation and puncture septic model and folic acid-induced AKI, cyclosporine A, a known cell cycle arrest inducer attenuates AKI [53, 54].
\nIn human, Kashani and colleagues propose biomarkers of cell cycle as an early biomarker of AKI [55]; tissue inhibitor of metalloproteinases-2 (TIMP-2), a natural inhibitor of the group of matrix metalloproteinase, and insulin-like growth factor-binding protein 7 (IGFBP7). IGFBP7 regulates the availability of insulin-like growth factor and stimulates cell adhesion. In addition, both TIMP-2 and IGFBP7 are responsible for several molecular pathways, including oxidative stress, detoxification, and inflammatory responses. Therefore, they represent the early stage of any stresses that affect kidney. After tubular cells injury, IGFBP7 directly increases the expression of p21 and p53. Simultaneously, TIMP2 enhances p27 expression through an autocrine and paracrine manners. All of these p-proteins block the functions of the cyclin-dependent protein kinase complexes (CyclD-CDK4 and CyclE-CDK2) during the cell-cycle promotion process. G1 cell-cycle arrest occurs momentarily for avoiding cell division during the injury, and this alarm could send to adjacent cells as paracrine effect. This mechanism needs further exploration. More recently, a new interesting hypothesis mentioned that all of the injuries are the results of the cell maladaptation to an insufficient energy condition [56]. More studies are needed to support this interesting hypothesis.
\nIn the real clinical situations, multiple mechanisms in combination might be responsible for the individual patient. Therefore, a mechanistic approach to patients with SA-AKI needs the integration and understanding of these mechanisms. The biomarkers for detecting these events might be helpful for sepsis mechanistic approach in the future.
\nClinical presentation of SA-AKI is completely uncertain especially in the early phase of sepsis. SA-AKI may develop simultaneously with sepsis or follow by sepsis. Therefore, physicians must be alert of SA-AKI when encountering with sepsis patients and vice versa—during evaluation of patients with AKI. In clinical practice, the individual baseline characteristics of patients are very useful for the proper SA-AKI management. Signs and symptoms of sepsis in individual patients depend upon individual susceptibilities and are usually masked by the organ involvement. As mentioned earlier, the SA-AKI diagnosis depends on SCr (absolute increase of SCr concentration of 0.3 mg/dL over 48 h or a relative change in SCr concentration of 1.5- to 1.9-fold to baseline over 7 days) or UO (less than 0.5 mL/kg/h for 6 h). SCr measurement, however, is insensitive indicator of AKI due to the time dependence accumulation. In mice with bilateral nephrectomy, SCr increases from baseline as late as 12–18 h after surgery [33]. According to SCr half-life (t\n½), increments in SCr concentration lag the decrements in GFR by an hour. In addition, sepsis leads to the reduction in muscular production of creatinine from inflammatory process. And diuretic administration in AKI for promoting the non-oliguric phase results in the unreliable UO criteria. Thus, other biomarkers in addition to SCr and UO are required. Urine analysis and urine biochemistry indices may be useful as adjunctive biomarkers to support or differentiate SA-AKI. The presence of urine granular cast and renal epithelial cells is not only for the differentiation between pre-renal AKI and ATN but also for SA-AKI versus non-septic AKI [57]. Urinary sediment examination remains a classic, cost-effectiveness, and worthwhile method for the differentiation of AKI etiologies. By contrast, urine chemistry indices including urine sodium (UNa), fractional excretion of sodium (FENa), and fractional excretion of urea (FEurea) are beneficial for the differentiation of pre-renal AKI from acute tubular necrosis (ATN) but unfortunately unable to differentiate between SA-AKI versus non-septic AKI. However, Vanmassenhove et al. [58] demonstrates that low FENa and low FEurea are predictive of transient AKI and oliguria is predictive for impending AKI in early sepsis. Although some studies demonstrate the benefit of urine chemistry indices in SA-AKI, there is still no established urine chemistry test to differentiate SA-AKI from non-septic AKI.
\nAs such, the quest for novel biomarkers as an earlier assessment tool for detecting SA-AKI is crucial. Such biomarkers are categorized into two groups: (i) the determination of renal functions and (ii) the detection of renal cell injury. Some lists of candidate new biomarker of SA-AKI are cystatin C (Cys-C), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), liver-type fatty acid-binding (L-FABP), soluble-triggering receptor expressed on myeloid cells-1 (sTREM-1), and activating transcriptional factor 3 (ATF-3). The sensitivity and specificity of these biomarkers vary depending on the timing of measurement and clinical samples. Generally, blood (serum) biomarkers show a lower sensitivity for AKI diagnosis than urinary biomarkers [59, 60]. NGAL is currently the most considered biomarker in AKI. However, it is non-specific to AKI and may be increased by activated neutrophils due to the response of systemic infection. We have demonstrated the benefit of NGAL and Cys-C in SA-AKI with bilateral nephrectomy and bilateral ureter obstruction models [33, 61]. Cys-C is generated from all nucleated cells and NGAL produced from several organs (lung, heart, kidney, and spleen). Because NGAL is reabsorbed from proximal tubules but produced from distal renal tubules [62], NGAL is not only a biomarker of proximal tubular function but also a biomarker of renal injury. Although both molecules are not specific for kidney, NGAL and Cys-C increase more rapidly than SCr after bilateral nephrectomy, possibly due to the more intrinsic sources in the body than SCr. While SCr is generated from muscle due to the utilization of creatine, these molecules are generated from several organs including muscle. It is interesting to note that renal NGAL, as determined by Western blot analysis, after bilateral ureter obstruction, does not increase as rapidly as serum NGAL [33]. This implies the possible limited utilization of kidney-specific NGAL (monomeric form of NGAL) for SA-AKI diagnosis. It is also interesting to note that sepsis does not enhance the production of creatinine, NGAL and Cys-C. SCr and Cys-C after CLP in bilateral nephrectomized mice are lower than CLP in normal mice. And serum NGAL in bilateral nephrectomized mice is not different to the level of CLP in normal mice [33]. In this aspect, among these biomarkers, SCr has several limitations and NGAL is the best representative for SA-AKI in these mouse models.
\nFor other biomarkers, urine IL-18 is a cytokine that respond not only to AKI but also to inflammation and infection. Urine L-FABP has been reported as a good predictor of mortality in patients with sepsis in ICU and shows the significant higher level in SA-AKI in comparison with sepsis-non-AKI [63]. In addition, urine exosome is another interesting source of candidate AKI biomarkers. Exosome is the nanosize vesicle containing molecules from cytoplasm or nuclei surrounded by some parts of cell membrane [62, 64–66]. Exosome is another mechanism of cell-cell communication possibly aiming to deliver non-soluble molecules and/or ligands of cell membrane receptor. As such, MHC-containing exosome could activate other immune cells in a distance without the necessary for the close proximity activation [64]. Moreover, several rapid-degradable molecules (RNA, miRNAs) or molecules of intra-nuclei (e.g., transcriptional factors) could be protected and delivered by exosome. Likewise, our group recently demonstrates the role of urine exosomal ATF-3 as a good additional biomarker for determining the onset of AKI in sepsis [62]. The summary of promising urine and serum biomarkers for SA-SKI is shown in \nTable 1\n. Although only a single biomarker might be already useful for SA-AKI determination, the combination would be even more beneficial in the clinical practice. For examples, an increase in biomarkers of injury but not biomarkers of renal function could represent subclinical AKI (normal SCr). And an increase in functional biomarkers but not biomarkers of cell injury may represent CKD. More studies are needed.
\nIndices | \nTiming of measurement | \nAUROC | \nThreshold values | \nSensitivity | \nSpecificity | \nReferences (year) | \n
---|---|---|---|---|---|---|
\nUrine biomarker(s)\n | \n||||||
NGALa (ng/mg creatinine) | \n12-h following septic shock | \n0.86 | \n>68 | \n0.71 | \n1.0 | \nMartensson et al. [72] (2010) | \n
sTREM-1a (pg/mL) | \n48-h before AKI diagnosis* | \n0.92 | \n69.04 | \n0.94 | \n0.76 | \nSu et al. [73] (2011) | \n
Cys-Ca (mg/L) | \nWithin 8 days after admission | \n0.86 | \n0.106 | \n0.85 | \n0.80 | \nAydoğdu et al. [60] (2013) | \n
NGALa (ng/mL) | \n\n | 0.80 | \n29.5 | \n0.88 | \n0.73 | \n\n |
NGALa (ng/mL) | \n7 days after onset of sepsis | \n0.86 | \n402 | \n0.89 | \n0.74 | \nFan et al. [74] | \n
NGALa (ng/mL) | \n24 h after admission | \n0.78 | \n350 | \n0.75 | \n0.82 | \nMatsa et al. [75] (2014) | \n
α1ma (mg/L) | \n24 h before AKI onset | \n0.74 | \n47.9 | \n0.88 | \n0.62 | \nTerzi et al. [76] (2014) | \n
Cys-Ca (mg/L) | \n24 h before AKI onset | \n0.74 | \nN/A | \nN/A | \nN/A | \nDai et al. [77] (2015) | \n
NGALa (ng/mL) | \n\n | 0.88 | \nN/A | \nN/A | \nN/A | \n\n |
sTREM-1a (pg/mL) | \n\n | 0.78 | \nN/A | \nN/A | \nN/A | \n\n |
ATF3a (ng/mL) | \n24 h before AKI onset | \n0.84 | \n12 | \n0.93 | \n0.85 | \nPanich et al. [62] (2017) | \n
NGALb (ng/mL) | \n\n | 0.64 | \n150 | \n0.98 | \n0.44 | \n\n |
\nSerum or plasma biomarker(s)\n | \n||||||
NGAL (ng/mL) | \n12 h following septic shock | \n0.67 | \n>120 | \n0.83 | \n0.50 | \nMartensson et al. [72] (2010) | \n
Cys-C (mg/L) | \nWithin 8 days of admission | \n0.82 | \n1.5 | \n0.73 | \n0.68 | \nAydoğdu et al. [60](2013) | \n
NGAL (ng/mL) | \n\n | 0.44 | \nN/A | \nN/A | \nN/A | \n\n |
NGAL (ng/mL) | \n24 h after admission | \n0.88 | \n400 | \n0.79 | \n0.75 | \nMatsa et al [75](2014) | \n
Presepsin (pg/mL) | \nWithin 24 h of admission | \n0.70 | \n670 | \n0.70 | \n0.81 | \nNakamura et al. [78] | \n
Procalcitonin (ng/mL) | \nWithin 24 h of admission | \n0.88 | \n0.42 | \n0.95 | \n0.65 | \nNakamura et al. [79](2015) | \n
Cys-C (mg/L) | \n24 h before AKI onset | \n0.74 | \nN/A | \nN/A | \nN/A | \nDai et al. [77] (2015) | \n
NGAL (ng/mL) | \n\n | 0.83 | \nN/A | \nN/A | \nN/A | \n\n |
sTREM-1 (pg/mL) | \n\n | 0.75 | \nN/A | \nN/A | \nN/A | \n\n |
Summary of the published studies in early urine and plasma biomarkers for detecting SA-AKI.
*No data were available 24 h before AKI onset.
aDetection from urinary soluble fraction part.
bDetection from urinary exosomal part.
α1m, alpha-1-microglobulin; AKI, acute kidney injury; ATF3, activating transcriptional factor 3; AUROC, area under the receiver operating characteristic curve; Cys-C, cystatin-C; N/A, data not available; NGAL, neutrophil gelatinase-associated lipocalin; sTREM-1, soluble-triggering receptor expressed on myeloid cells-1.
The discovery of early biomarker of SA-AKI not only improves the clinical management strategies but also adds up the understanding in the pathophysiology of SA-AKI. Unfortunately, SA-AKI pathophysiology in patients is not straightforward. Several comorbidities and the exposure to other AKI inducers (radiologic contrast-media (contrast-induced nephropathy), antibiotics (nephrotoxic ATN or acute interstitial nephritis), and hypotensive state (ischemic ATN) enhance the complexity of sepsis in patients. Hence, the major molecules responsible for SA-AKI in each patient might be different and the different approach and therapies might be necessary. For an example, SA-AKI with the predominant of HMGB1 versus high activated protein C might require the different managements. Therefore, it might be difficult to recognize the molecular responses of SA-AKI only by patient history or current biomarkers. More serum, urine, or tissue biomarkers should be beneficial. Thus, appropriate techniques of renal biopsy in an appropriate time point of SA-AKI might be helpful for an early diagnosis and exploration of the individual molecular responses. This approach could be one of the strategies for “sepsis-individualized therapy.” As such, numerous renal biopsy techniques have high yields, safe and effortless [67, 68]. The studies of renal biopsy in the selected case of patients with AKI will be very interesting.
\nIn addition, the interpretation of some non-renal biomarkers in AKI should be cautious. For examples, cardiac troponin I, a biomarker of cardiac muscle injury, is usually high in patients with abnormal renal function [69]. Troponin I of >0.8 ng/dL or the alterations from baseline level or additional use of other biomarkers (e.g., myocardial creatinine kinase; CKMB) might be helpful to determine cardiac cell injury. Fluid status in SA-AKI could affect N-terminal pro-B-type natriuretic peptide (NT-BNP) and troponin T [70]. We also explore microRNA-122 (miR122), a new liver injury biomarker, in several mouse models including sepsis [71]. We found that miR-122 is not superior than alanine transaminase (ALT) for the detection of sepsis-induced liver injury.
\nSimilar to general managements in sepsis, SA-AKI treatment bases upon the rapidly appropriate antibiotic administration and best supportive cares. Here, we summarized the important points in SA-AKI management.
\nFluid administration is the corner stone of resuscitation especially in sepsis. Theoretically, fluid responder defines by a patient whose stroke volume (SV) increases by 10–15% after a fluid challenge (250–500 mL) [80], but less than 40% of septic patients are fluid responders [81]. According to Frank-Starling principle, as the preload increases, SV increases until the optimal preload is achieved. Thus, if the fluid challenge does not increase SV, the amount of volume loading would be harmful from the increase in arterial pressure, venous pressure, and, in the end, pulmonary hydrostatic pressures. Moreover, these responses stimulate the release of natriuretic peptide that induces fluid shift from intravascular portion into interstitial space. Of note, kidney is also particularly affected by increased venous pressure resulting in increased renal subcapsular pressure and decreased GFR.
\n“Fluid expansion as supportive therapy” (FEAST) is the most explicit study that demonstrates the harmful of fluid loading in sepsis [82]. In this randomized study, aggressive fluid loading is associated with an increased risk of death. After the concept of early aggressive fluid resuscitation—“early goal directed therapy” (EGDT)—published in 2001 [83], a number of studies using EGDT protocol have been published subsequently [84–86]. Interestingly, these studies show an obvious reduction in mortality rate, especially during 2010–2015, which associates with the decline in the volume of fluid resuscitation in the first 72 h. Although the fluid resuscitation in an early phase of sepsis with a significant decrease in effective circulatory volume sounds reasonable, the ongoing fluid maintenance therapy remains in trouble, particularly in SA-AKI [87]. Fluid therapy, moreover, is not only incapable of effective reverse septic shock but also contribute to the more renal dysfunction through several mechanisms. For instance, an increased venous pressure following fluid therapy directly increases pressure in renal interstitium and peritubular area in animal models [88]. Because a large fluid bolus (20–30 mL/kg) is associated with volume overload, the approach with the less volume of fluid bolus (200–500 mL) is currently recommended [89]. Acute dialysis quality initiative (ADQI) suggests the approach of fluid therapy in sepsis by dividing into four stages: rescue, optimization, stabilization, and de-escalation [5]. High-volume resuscitation is needed during the rescue stage followed by optimization and stabilization protocol depending on the individual patient. After that, the de-escalation consists of reduced total fluid water in patients where diuretics and/or renal replacement therapy (RRT) might be necessary. Regarding fluid therapy monitoring, passive leg-raising maneuver (PLR) after fluid bolus combined with the real-time SV measurement is the only procedure with a high clinical accuracy of fluid status [80, 89]. Due to the availability of ultrasonography in most of the ICUs, the exclusion of fluid overload by the real-time detection of B-line and abnormal curtain sign in the lung, the vena cava collapsibility by M-mode ultrasonography, and the abnormalities in cardiac function is noninvasive and might be helpful as the additional information in the real clinical situation. But these procedures are operator dependent that need a special training. Nevertheless, physical examination, central venous pressure (CVP), central venous oxygen saturation (ScvO2), chest radiography, and the vena-caval collapsibility index by ultrasonography show limited value in fluid monitoring and is not generally recommended for fluid challenge purpose [90–92]. It might be important to note that in patients with previous normal blood pressure, the mean arterial pressure (MAP) at 65–70 mmHg might be adequate for maintaining renal perfusion. But MAP at 80–85 mmHg might be needed in patient with a history of hypertension [93]. Moreover, serum lactate should be less than 2 mmol/L. The new definition of septic shock from the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), the stage with the need of vasopressor from maintaining MAP ≥65 mmHg and serum lactate more than 2 mmol/L, implies the importance of serum lactate and vasopressor in clinical practice [1].
\nIn addition to the amount of volume, fluid composition is another issue that must be considered in SA-AKI. Normal saline (0.9% NaCl), a non-physiologic solution, is possibly less beneficial in SA-AKI than other new fluid preparations. Normal saline causes a hyperchloremic metabolic acidosis resulting in decreased renal blood flow (by activation of TG feedback mechanisms and afferent vasoconstriction) and increases the risk of further renal injury [94, 95]. Moreover, normal saline is associated with an increased risk of death in comparison with physiologic salts solution. Similarly, synthetic hydroxyethyl starch is potentially nephrotoxic and not recommended in SA-AKI patients [96]. Blood transfusion is used to improve microcirculatory hemoglobin and tissue oxygenation. However, the results of blood transfusion in reducing morbidity and mortality remain inconclusive [96, 97]. Despite theoretical disadvantage of normal saline in SA-AKI, the result from randomized control trial is still controversy. Moreover, normal saline is generally available in a reasonable price worldwide. Thus, normal saline should still be a main fluid replacement used in SA-AKI. However, the alternative administration of normal saline with other fluid preparations or the limited volume of normal saline might be more beneficial. Recently, Steward approach on acid-base proposed the ratio of serum chloride/sodium (SCl/SNa) at higher than 0.76 as the indication of chloride access and the timing for the replacement of normal saline into other solutions [98]. More studies are needed.
\nAcidosis is common in patients with sepsis which might be due to lactic acidosis, respiratory acidosis, and/or hyperchloremic metabolic acidosis from high volume of normal saline. But bicarbonate treatment is not recommended unless blood pH is lower than 7.15. Sodium bicarbonate infusion leads to hypernatremia, hypervolemia, intracellular shift of calcium-induced hypocalcemia, intracellular acidosis, and impaired oxygen delivery [99]. Improved tissue perfusion, proper respiratory machine adjustment, and balance administration of high-volume normal saline with other fluid therapy (e.g., other balance solutions) should be helpful. Tris-hydroxy methyl amino methane (THAM), a weak base with intracellular diffusion, might be beneficial due to the lower intracellular acidosis in comparison with bicarbonate infusion. However, THAM causes hyperkalemia, hypoglycemia, pseudohyponatremia, and increased osmolol gap in patients with preexisting renal dysfunction due to the excretion through kidney [100].
\nThe rapid control organism is still the main theme of sepsis treatment. The survival rate of patients with sepsis declines 7.6% for every hour of delayed appropriate antibiotic treatment [101]. Regarding AKI from antibiotic, vancomycin is reported to induce AKI despite appropriate therapeutic level (15–20 mg/dL; the recommended level for the treatment of methicillin-resistance Staphylococcus aureus (MRSA)). Vancomycin is also reported to enhance nephrotoxic of piperacillin-tazobactam [102]. Although these events might be due to the contaminants, vancomycin administration in a high dose should be careful and blood level monitoring might be helpful. Other unnecessary nephrotoxic substances, such as amphotericin B, iodinated contrast agents, and so on, should be avoided. In addition, there is only a report of gadolinium (a contrast for MRI)-induced AKI [103] but several reports on increase incidence of nephrogenic systemic fibrosis in gadolinium injection in patients with preexisting renal injury.
\nIn SA-AKI, the alteration of vascular tone is a major cause of hypotension and renal injury. Norepinephrine maintains mean arterial pressure and increases renal medullary circulation without RBF alteration leading to improved renal function both in animal models and in human [93, 104–106]. Norepinephrine also restores normal capillary velocity and filtration pressure [107]. Thus, norepinephrine is the first-line drug for septic shock. On the other hand, iloprost, a vasodilatory prostacyclin, has been considered to reduce cortical microcirculatory hypoxia and preserve renal function in animal model of SA-AKI [108]. But the clinical data on the efficacy and safety of iloprost administration are still limited.
\nThe general four concerning aspects of renal replacement therapy (indications, timing, modality, and delivered dose) and the traditional clinical indications of RRT (“A-E-I-O-U”; A-acidosis, E-electrolyte disturbance, I-intoxication, O-fluid overload, and U-uremia) should be applied to SA-AKI as other causes of AKI. Indeed, severe metabolic acidosis, fluid overload, and uremia are the top three common indications for RRT in SA-AKI.
\nRegarding the timing of RRT initiation, the data are heterogeneous, inconclusive, and centers dependence. Although adverse effect of delayed RRT initiation has been reported with a higher mortality rate and worse renal outcome in SA-AKI [109], many consensus guidelines remain set as individual timing based on the only published randomized controlled trial. Bouman et al. [110] demonstrated non-significant differences in renal outcomes or patient survival between early and late initiation of hemofiltration. As such, the recently two large, high-profile randomized trials, specifically designed for the determination of RRT initiation in patients with AKI and critically ill condition, show the discordant conclusions [111, 112]. Single-center early versus late initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury (ELAIN) demonstrates the benefit of an early strategy of RRT initiation over a delay strategy in the mortality rate of critically ill patients [113]. Although eligible patients are at KDIGO stage 2, they have high sequential organ failure assessment (SOFA) score at 15.6–16.0. On the contrary, the artificial kidney initiation in kidney injury (AKIKI) study shows a negative result for early strategy of RRT initiation [114]. But patients enrolled in the AKIKI trial are at KDIGO stage 3 with SOFA score at 10.8–10.9 which is lower than the patients in ELAIN study. In addition, SOFA score in the renal component in AKIKI trial is also less than ELAIN study. Therefore, these two studies may have come to different conclusions because of the different inclusion criteria. The patients enrolled in the ELAIN trial are at an earlier AKI stage but more severe sepsis. Nevertheless, another trial for answering the optimal RRT timing is now ongoing—STARRT-AKI (standard vs. accelerated initiation of renal replacement therapy in acute kidney injury) study; clinicaltrial.gov NCT02568722.
\nThe choice of hemodialysis (HD) modality for patients with SA-AKI is also important to mention. Although the best choice of HD modality in SA-AKI remains inconclusive, only some studies showed the benefit of continuous renal replacement therapy (CRRT) over intermittent hemodialysis (IHD) in survival and duration before renal recovery [115, 116]. Regarding CRRT in SA-AKI setting, continuous venovenous hemofiltration (CVVH) has recently demonstrated the promising results in comparison with extended daily hemofiltration (EDHF) [115]. Despite more severe sepsis (oliguria and severity of metabolic acidosis) of patients in CVVH group, they have a superior renal outcome on 60-day dialysis independence periods. However, a retrospective cohort study by AlEnezi et al. showed that CVVH does not attenuate mortality and length of hospital stay in comparison with continuous venovenous hemodiafiltration (CVVHDF) [116].
\nAlthough the benefit of renal recovery is superior in CRRT, over IHD, owing to the better fluid control with the fewer hypotensive episodes, CRRT is more expensive. On the other hand, on-line hemodiafiltration (Ol-HDF), an intermittent hemodialysis modality that increase mid-to-large molecular clearance by combining diffuse and convective transport with ultrapure dialysate, is a promising alternative modality for SA-AKI. Data from our study demonstrated that Ol-HDF not only benefits in renal support but also offers a potential role in immune modulation in SA-AKI [117]. The comparison of beneficial effects on renal outcomes and patient survival between CVVH and Ol-HDF in SA-AKI patients is ongoing in our center.
\nIn addition, optimal CRRT dose is evaluated in two clinical trials with nonspecific causes of AKI at an effluent rate of 25–30 and 40 mL/kg/h [118–120]. Although there is a tendency toward the reduced mortality rate in the higher dose of CRRT (40 mL/kg/h), it is not enough to reach a significant level. Likewise, the CRRT prescription dose at 30–35 mL/kg/h or 25% addition to the usual dose of CRRT is recommended by some centers to ensure an adequate delivered dose [121]. By theory, delivered CRRT dose over 35 mL/kg/h as known as “high-volume hemofiltration” may remove systemic inflammation and improve septic shock survival, but it is not supported by several clinical studies.
\nIt seems that CVVH has more benefit than IHD only in limited parameters with a significantly higher cost. Hence, we recommend IHD or sustained/slow low-efficiency dialysis (SLED) as a first choice of RRT modality followed by standard dose of CVVH (20–25 mL/kg/h) in SA-AKI depending on patient conditions. In addition, in the area with the limited resources, with less severe sepsis, and/or without other choices of RRT, peritoneal dialysis (PD) might be an alternative RRT modality [122]. However, the adequacy of PD in sepsis and the high glucose level in peritoneal dialysate is the major limitation of PD in sepsis. On the other hand, extracorporeal blood purification (EBP) is currently considered as one of the treatments for balancing homeostasis of sepsis immune responses. The absorption therapy with polymyxin B or other cytokine absorbents shows benefit in hemodynamic parameters and mortality rate in some studies [123] but still inconclusive. Therefore, the specific indication and/or proper biomarkers (i.e., stress-, injury-, functional loss-, and recovery biomarkers) to select patients with the highest probability to be beneficial from any treatment methods are urgently in need [124].
\nSepsis is often accompanied by acute renal failure, also called sepsis-associated acute kidney injury. The mechanisms by which sepsis and endotoxemia lead to SA-AKI are incompletely understood. However, growing evidences suggest that SA-AKI is a result of sustained renal microvascular hypoperfusion, insufficient cell energy, mitochondria dysfunction, endothelial injury, and cell cycle arrest. SA-AKI is associated with normal or even elevated renal blood flow, which is, at least in part, due to redistribution of blood flow from cortical to medullary region. Fluid therapy and proper antibiotics are crucial managements. Because too much fluid administration in sepsis increase organ dysfunction, hemodynamic-guided approach of fluid therapy and early vasopressor administration in SA-AKI would be beneficial. Currently, the role of renal replacement (RRT) in SA-AKI for renal support and immunomodulation has been evaluated. Although there is no consensus guideline, retrospective clinical studies have suggested that the early initiation of RRT and the use of continuous methods are associated with a better hemodynamic tolerance and renal outcome. Timing and dose of RRT are ongoing debate, yet recently randomized clinical trials remain unable to demonstrate any beneficial impacts of early RRT. In the future, we propose “sepsis mechanistic approach” as an individualized therapy for sepsis and the better matching between the results from the translational researches and the specific patient characteristics.
\nToday, information has become the main component of what we produce, do, buy, and consume. Having an economic value in almost all products and services that meet the needs of today’s societies, it has been now obligatory for individuals and organizations to obtain information technologies and to actively use them in both work and social life domains. Hence, in the current information age, where information is seen as power, this situation has made it imperative for organizations to become increasingly information-based and to benefit from information technologies in many processes and activities.
The intensive use of information technologies in many functions and processes has also required some changes in organizations [1]. This is due to the fact that information technologies, unlike traditional technologies, do not only change the technical fields but also affect the communication channels, decision-making functions and mechanisms, control, etc. [2]. Consequently, one of the most striking developments is on organizational structures that are becoming increasingly flattened and horizontal. Relatedly, information technologies have begun to take over the role of middle management, which supports decision-making processes of senior management and has reduced the importance of this level [3, 4, 5]. Similarly, while information technologies enable managers to obtain faster, more accurate, and more information [6, 7, 8], it also provides lower-level managers with more information about the general situation of the organization, the nature of current problems, and important organizational matters [9, 10, 11, 12].
Moreover, information technologies also have an important potential in determining whether organizations have a mechanical or an organic structure [13]. Within the mechanical organizational structures, people do not have much autonomy, and behaviors expected from employees are being careful and obedience to upper authority and respect for traditions. In such organizations, predictability, consistency, and stability are desirable phenomena. In contrast, people in organic structures have more freedom in shaping and controlling their activities, and being enthusiastic, creative, and taking risks have important places among the desired behaviors [14].
Accordingly, information technologies begin to influence the cultural values of the organization over time, through these transformations they create on organizational structures, processes, and operations. In other words, the fact that organizational structures are mechanical or organic causes the formation of diverse cultural values in organizations [15]. Therefore, the desired cultural values in mechanical organizations are quite different from those in organic structures [1, 16, 17]. In this context, this chapter deals with the influences of information technologies on cultural characteristics of organizations along with the reflections of the use of these technologies on organizational structures and their functioning.
When we look at studies on the relations between organizational culture and information technologies, we generally see the studies on the effects of culture on technology adaptation or use [18, 19, 20, 21], as well as on the effects of certain specific information technologies and applications (e.g., e-mail use, group support practices, etc.) on some aspects of any organizational culture [22, 23, 24, 25, 26, 27, 28, 29, 30, 31]. However, the number of studies that consider the use of information technologies as a “whole” and that address “why” and “how” its effects on organizational culture occurred is still limited. And so, this chapter aims to examine and discuss the overall effects of the usage and intensity of information technologies established in organizations on the cultural life within.
In this context, the chapter plan is as follows: Firstly, the basic concepts related to information and information technologies are included. Emphasis is placed on the meaning differences between knowledge and information, and their connections to information technologies are tried to be explained briefly. Secondly, the effects of information technologies on organizational structure are given particular attention. The reason for this is that as a system of values, beliefs, assumptions, and practices [32], organizational culture encompasses many features closely related to structures of organizations. Thirdly, possible links between organizational structure and organizational culture are included. Fourthly, important theoretical approaches and studies on the relationships between information technologies and organizational culture are provided. Finally, by deepening a bit more and by emphasizing key points, some important arguments are discussed.
In the literature, the concepts of information and knowledge are sometimes expressed by a single term, “information.” However, although the concepts of knowledge and information are intertwined, they are two different concepts that have different meanings and describe different phenomena. The reason for this is that knowledge is also included in the concept of information as it is transformed into a commodity when it begins to be processed, stored, and shared by information technologies.
Becoming the basic elements of today’s economic, social, and cultural systems, information is obtained in a certain hierarchy. The images are at the beginning of the process, and the process is completed with a hierarchical staging in the form of data, information, and knowledge, respectively [33]. Image is located in the first step of the process. Humans copy the picture of any object and event they previously perceived by sensory organs. When faced with a similar phenomenon in the later stages of life, these pictures in the mind are redesigned. We call these pictures of realities occurring in the human mind as images [33]. The next stage, the data, contains symbols that represent events and their properties. For this reason, data are expressed as figures and/or facts without content and interpretation [34]. Information that constitutes the next stage of the process and is mixed with knowledge and used interchangeably is expressed as a reporting of one system’s own status to another system [33]. In information, associated data are combined for a specific purpose. Therefore, we can explain information as meaningful data [35]. Knowledge, on the other hand, is defined as personalized information that allows people to fully and accurately grasp what is happening around them and manifests itself in the form of thoughts, insights, intuition, ideas, lessons learned, practices, and experiences [36]. According to Kautz and Thaysen [37] who stated that knowledge is found only in the people’s minds, knowledge is, therefore, a subjective formation. In other words, knowledge is the form of information enriched with interpretation, analysis, and context [38]. However, here, it should be emphasized again by highlighting a very important issue that knowledge is also accepted as information when this knowledge begins to be processed, stored, shared, and used over information technologies. Therefore, after this, when talking about information, one should consider not only the information created by the data brought together in a meaningful way but also the knowledge shared and used over information technologies.
On the other hand, information technologies, used as the most important tool of generating value today, are defined as the technologies that enable processes such as recording and storing data, producing information through certain operational processes, and accessing, storing, and transmitting this produced information effectively and efficiently [39, 40, 41, 42, 43, 44, 45, 46]. The term information technologies is used to cover computer and electronic communication technologies, as they are now inseparably intertwined in literature and everyday use and are generally used in this way [47]. In this context, data processing systems, management information systems (MIS), office automation systems, executive support systems, expert systems, intranet and extranet, electronic mail (e-mail), group applications (groupware), database management systems, decision support systems, artificial intelligence, and telecommunication systems can be given as examples of information technologies [33, 48, 49].
Towards the end of the twentieth century, the rapid changes with the impact of developments in information technologies led to the emergence of customer satisfaction-based, learning, knowledge-based, and constantly changing organizations [50]. The fact that organizations have become considerably information-based and benefit from information technologies intensively in their activities and processes has made also the changes in their organizational structures mandatory [1]. Accordingly, the effects of information technologies on organizational structure will be summarized under the subtitles of differentiation, centralization, and standardization/formalization, which are the three main components of organizational structure [15].
Differentiation within an organization occurs in three ways: Specialization/division of labor, horizontal and vertical differentiation, and hierarchy and size [15]. Specialization refers to the amount of different expertise or types of work [51, 52]. Specialization generally increases the number of subunits and makes it harder to understand the larger structure that people contribute to with their skills and expertise [53]. Information technologies have the potential to reduce this tendency by providing more access to information and experts at this point. In this way, access to information resources provides synergy [54].
Vertical and horizontal differentiation refers to the amount of hierarchical levels in an organization [55]. Information technologies, with the support of problem solving and decision-making, lead to the emergence of more flattened organizational structures as they require fewer levels within the hierarchy [56]. Since information technologies give employees in lower positions more autonomy to harmonize their activities, this can allow them to find and try better methods while performing their work. In this context, we can increasingly see that organizational structures have become horizontal and strengthened and that virtual organizations have begun to emerge as the most cost-effective structure [17].
In terms of hierarchy and size, Heinze and Stuart [4] argue that the mid-level management staff is unnecessary, increases bureaucracy, reduces efficiency, and has no function in organizations any more. Since most of the tasks performed by mid-level executives can be fulfilled by computers, both less costly and faster, information technology has begun to take over the role of mid-level management, which supports the decision-making process of senior management [5]. Sharing the same opinion, Fulk and DeSanctis [57] also stated that the largely witnessed situation in modern organizational designs is the reduction of intermediate-level managers and administrative support.
Centralization points to the extent to which decision-making power within an organization is scattered or centered [58]. Due to increasing local and global competition, many companies have started to leave their strategic decision-making task further down the organization to benefit from the expert people with more precise and timely local knowledge [10]. Information technologies affect these efforts directly in two ways. Firstly, information technologies increase local knowledge by contributing to obtaining closer information about market trends, opportunities, and customers. Secondly, information technologies can create synergies for organizations because, thanks to information technologies, communication and coordination between distributed decision makers, central planners, and senior managers can be realized more effectively and efficiently [59].
However, whether information technologies will lead to centralization or decentralization is a very controversial question. Regarding centralization, it enables managers to acquire faster, more accurate, and more information, reduces uncertainty, and allows them to make decisions that they cannot make before [6, 7, 8]. Conversely, by the use of other forms of information technologies (e.g., electronic bulletin boards), decentralization provides more information to lower- and mid-level managers about the general situation of the organization and the nature of current matters and problems [9, 10, 11, 12]. Raymond et al. [60] argued that because information technologies facilitate the use and transmission of information by all levels and units in the organization, it enables top management, which is the decision authority, to be disabled in certain areas and the decentralization of control. Thach and Woodman [61] maintained that this is due to the fact that as a result of sharing information at lower levels with the help of information technologies, this power of senior management has decreased to a certain extent, and the knowledge and participation of the staff in organizational matters have increased.
The literature shows that information technologies allow both centralization and decentralization. Researchers are in the agreement that information technologies make it possible for organizational managers to leave their decision-making power to a large part of the hierarchical levels without compromising the quality and timeliness of the decision [62, 63]. Keen [64] combined the concepts of centralization and decentralization and used the term “federated organization” in which organizations do not have to choose either because information technologies simultaneously allow centralization-decentralization [64, 65].
Formalization is the process of detailing how activities are coordinated for organizational purposes in order for employees and organizational units to respond routinely to recurring situations [51, 66]. Formalization involves rules, instructions, shared values, and norms [67]. In fact, formalization is based on the objective of more efficiency and less uncertainty [13].
Information technologies provide the ability to reduce the negative effects of formalization by facilitating the documenting and retrieving of information on organizational occurrences and endeavors that make behaviors and processes more consistent through formalization [63]. The more information technologies assist in reducing search times and preventing downtime, the more the administrative cost of formalization decreases and the productivity increases, which ultimately benefits the path to innovation [68].
Different organizational structures lead to the development of different cultural values [15]. The fact that the structure which an organization has established to control its activities and is defined as a formal system consisting of duties and authority relations is mechanical or organic causes the emergence of completely different cultural values, rules, and norms [69]. While mechanical structures are vertical, highly centralized, and almost everything in them are standardized, organic structures are horizontal, decentralized, and based on mutual adaptation [14]. People feel relatively less autonomous in vertical and centralized organizations, and being careful, obeying the upper authority, and respecting traditions are among the desired behaviors. Therefore, in a mechanical organizational structure, there are cultural values where predictability and stability are important [69]. In contrast, in horizontal and decentralized organizations, people can freely choose their own activities and control them. Creativity, courage, and risk-taking are given importance as desired behaviors. Therefore, organic structures contribute to the formation of cultures that value innovation and flexibility [15].
Organizational structure is also important for the development of cultural values that support integration and coordination. In a structure with stable task and role relations, sharing of rules and norms is more since there will be no communication problems and the information flow will be fast [70]. In organizations where the sharing of cultural values, norms, and rules is at a high level, the level of performance also increases [15]. Particularly in team or matrix structures where face-to-face communication is intense, the sharing of these cultural values and common reactions to the problems develop more rapidly [9].
Whether an organization is centralized or not causes different cultural values to emerge. In decentralized structures, authority is divided into subordinate levels, and an environment is created for the formation of cultural values in which creativity and innovation are rewarded [13]. Employees are allowed to use the organization’s resources and work in projects that they want, by spending some of their time in these projects, thus contributing to the production of innovative and creative products and services [15]. The structures of such organizations constitute the cultural values that give their employees the message “as long as it is in the interest of the organization, it is okay to do things in an innovative and the way you want.”
Conversely, in some organizations, it may be more important for employees not to decide on their own and all activities to be followed and controlled by their superiors. In such cases, a centralized structure is preferred to create cultural values that will ensure accountability and obedience [71]. Through norms and rules, all employees are expected to behave honestly and consistently and inform their superiors about wrongs or mistakes, because this is the only acceptable form of behavior within these structures [72].
Since working on the factors that determine the consequences of the adoption and use of information technologies, researchers have focused on people’s beliefs, values, assumptions, and codes of conduct. As a result, they have given names to this research field such as “socio-technical systems,” “social system,” “social structure,” and most recently “culture” [73]. For example, Markus and Robey [23] using “social elements” and Barley [26] using “social system” or “social structure” tried to explain this phenomenon. When examined more closely, it is seen that the details that these authors emphasize while depicting the case are the assumptions, beliefs, and values that exist in common among the group members, and this corresponds to the definition of organizational culture.
Research examining the relationships between information technologies and values, beliefs, and norms belonging to a particular group has gone through certain stages and used rich and complex research models to explain the relationships in each of these stages [74]. In the first studies on information technology applications, it has been suggested that information technologies cause changes in various organizational phenomena including structural features and thus have certain effects on organizations [74]. For instance, in some studies on adoption of groupware software, several researchers have used this deterministic approach to describe how groupware use affects communication and collaboration among employees and their productivity [27, 28]. These studies assume that certain results will certainly emerge after the adoption of information technologies, without considering the motives or activities that shape the use of information technologies by managers and employees. Like much more deterministic studies, these authors often assumed that information technologies would have predetermined influences on the adoption of information technologies, regardless of the environment in which information technologies were applied, how they were applied, and the users’ specific behaviors and particular purposes.
The second group of views concerning the relationships between organizational culture and information technologies includes the fact that information technologies are seen as a tool that can be used for any change that managers desire to make in organizational practices [22]. In studies in this approach, researchers believe that there is a wide range of possibilities to identify changes in organizational culture, structure, processes, and performance [22, 75]. Researchers from this tradition presume that with the right choice of information technologies and appropriate system design, managers can achieve whatever goals they desire.
These works were mostly adopted in the 1980s and reflect a perspective that managers think can manipulate organizational culture in the way they want. Often called “management and control,” “a functional or instrumental approach” to organizational culture, this methodology has caused serious debate in the literature [76]. This approach attributes great powers to the management level in this regard, which conflicts with anthropologists’ views that culture cannot be consciously controlled and goes much deeper to understand it [76]. Robey and Azevido [77] also do not accept the rational thought on the assumption that culture can be manipulated directly in this way.
Studies with this rational perspective in the information technology literature assume that managers can use information technologies as a leverage to make changes in the norms of behavior, strategy, structure, and performance among members within the organization. For example, in studies on group support systems (GSS), we find managers’ beliefs that they can use collaborative technologies to create a more cooperative organizational culture. This perspective was not accepted by Karsten [78] and some experimental research on GSS [30, 79]. Organizational necessity is no longer accepted, as it is viewed by information technology researchers as an overly simple approach [23, 80].
Researchers who take another approach suggest that information technologies and organizational culture can interact with each other to produce various results [22, 23]. These results can be in the form of adoption and effective use of information technologies (if there is a harmony between organizational culture and information technologies) or user reluctance, refusal, or sabotage (if no fit). Researchers who have been working on information systems since the 1980s have focused on understanding information technology features and functionality that cause effective or problematic information technology applications and the interaction between users’ values, assumptions, and other elements of organizational culture. In this regard, Romm et al. [81] argued that many forms of information technologies comprise cultural assumptions embedded within themselves and these assumptions may conflict with existing values of a particular organization. The authors argued that these embedded assumptions present information technologies as a “cultural boundary” and that a cultural analysis should be made to predict compliance or incompatibility. The authors in this approach warn managers to think of organizational culture as a binding limitation in information technology applications. In a warning by Pliskin et al. [76], managers are advised not to try to change the culture of the organization. Regarding this issue, Orlikowski [30] cites Lotus Notes (a group software) application at Alpha Corporation, a consultancy company. In this example, this system, which was established by the CEO of the company only with the benefits to be obtained, did not create the expected effects, became unsuccessful, and disappointed due to reasons such as no cultural analysis and inadequate training. Employees responded to the use of Notes with resistance and refrained from using it. The reason for this was that the employees in this organization, which had a competitive culture where information was seen as a power, avoided sharing information with others. As a result, this incompatibility between the collaborative culture that Notes had in itself and the competitive culture of the organization in question had failed this application of information technologies.
In a different approach, it is stated that information technologies and culture are not fixed and they are more flexible in terms of change [23, 75]. Managers in this approach may set specific goals for the use of information technologies, but actual results of the use of information technologies are not deterministic, and results cannot be predicted or controlled even under the best conditions [23]. The effects of information technologies are not deterministic because technology has interpretable flexibility considering that it can have different meanings for different employees. Similar technology can be interpreted in a different way by distinct people, based on certain assumptions, beliefs, and values. Robey and coauthors [24, 25], for instance, showed that it would be an empty attempt for organizational managers to try to intentionally manipulate the effects of these technologies, since there are many ways that diverse employees can configure a particular technology in different social environments.
Gopal and Prasad [31] also achieved similar results in their work on group support system (GSS), claiming that for researchers seeking fixed laws or regulations on how information technologies affect user behaviors, this would be an impossible goal to pursue. Conversely, the results of using information technologies depend on the symbolic meanings that information technologies have for a particular user. This work of Gopal and Prasad [31] expresses similar results with the work of Barley [26] and Robey and Sahay [25]. The authors stated that the symbolic meanings of certain technologies for users affect their perceptions of information technologies and their specific behaviors.
In the light of the above-mentioned approaches, arguments, and important studies in the literature, it will be useful to discuss some important points by deepening a little more and by emphasizing the key features related to the concepts of information, information technologies, and organizational culture.
First, organizational culture is a complex phenomenon that develops and changes in a historical process [32, 82, 83]. Thus, although it might seem like a plain and simple concept, organizational culture includes many subdimensions and processes. When considered as a complex pattern of these interactions of many factors with each other, it is also a difficult process to identify the direct and indirect effects of information technologies on organizational culture within this cluster of relationships and interactions. Moreover, culture is not a phenomenon that changes and develops in a short time and is therefore open to manipulations of managers. On the contrary, from this point of view, it is not possible to easily achieve control over cultural changes, and it is necessary to go much deeper [76]. So, it is not rational to expect that the rapid developments and changes in information technologies will cause changes in cultural characteristics at the same speed. In this sense, it could be inaccurate to seek direct relationships between two phenomena in question, whose rates of change are quite different.
Second, for cultural changes, there must also be changes in the basic assumptions, beliefs, and values on which the culture is built [84]. It would be misleading to expect little or intensive use of information technologies to cause changes in these rooted assumptions. For the desired changes in these basic assumptions, beliefs, and values, it is necessary to design the structure accordingly, to recruit employees who are qualified for the targeted culture, and to set ethical values and property rights to employees in accordance with this culture [15]. In this sense, information technologies may only catalyze the contribution of organizational structure to organizational culture.
Third, there are many and different types of hardware and software that fall under the scope of information technologies. It is not logical to accept all of them as homogeneous technologies in all aspects (with the same functions and features, similar usage areas, standard conditions they are applied, similar intentions, and behaviors of all users), and it can be, therefore, misleading to carry out research under a single “IT” concept from this perspective. The reason for this is that, as stated in the sections above, cultural features of each information technology application or product embedded in it might be different. The interactions between the cultural characteristics of the environment in which information technologies are applied and the unique cultural contents of information technologies may cause different results on the culture of the organization.
Fourth, contrary to what is believed, some of cultural features that we anticipate to support information technology applications and products may be interpreted otherwise by diverse people contingent on different assumptions, beliefs, and values. In fact, Robey et al. [24, 25] showed that managers cannot control the effects of these technologies, since different users can configure a particular technology in numerous ways in different social environments. Also, Gopal and Prasad [31] argued that this would be an impossible achievement for researchers looking for fixed laws or regulations on how information technologies affect user behaviors.
Fifth, information technologies were defined above as technologies that enable processing, storage, and sharing of information. The key concept in this definition is “knowledge-based” information and not the technology itself. Therefore, what makes information technologies essential and important is the information itself. According to the definition of knowledge, the most significant characteristic that differentiates it from information is its being a product of the human mind [37]. Because knowledge is the interpretation of information and expresses the value produced from it, qualifying information technologies as good-bad, useful-useless, and necessary-unnecessary can be a meaningless evaluation. So, the basic thing that creates value-added for organizations is not the technology used but the information itself, which is processed, stored, and shared on this technology. In this context, even if it is the latest, most advanced, and most expensive technology in the world, if the organization does not have a qualified human resource capable of producing knowledge that will create value-added, an appropriate organizational structure and culture that will activate this creative potential, and a management approach, all investments in these technologies will also be wasted.
This chapter has aimed to examine the impacts of information technologies on organizations’ cultures, and for this purpose, a special emphasis is given to the concept of “organizational structure” within the theoretical framework presented above. The most important reason for this is that relevant literature shows that organizational culture and organizational structure are in a very close relationship. Indeed, when the question items in the Denison organizational culture scale [85], which is the most frequently used in the literature, are examined, it is possible to see that most of these items point to many features of organizational structure concerning centralization, formalization, and differentiation dimensions. Therefore, it is a very rational approach to expect that information technologies can have direct and indirect effects on organizational cultures based on the influences of information technologies on structures of organizations. However, it should be underlined that different and controversial approaches and findings in the literature mentioned above on the relations between information technologies and organizational culture generate question marks in the minds as well.
In this regard, it is already quite difficult to draw a clear picture of the impacts of information technologies on cultural characteristics of organizations. The number of studies on the subject in the literature is still very limited. Accordingly, it is necessary to underline the great need for interdisciplinary studies in this field. But still, this study argues that the main factor that determines the actual impact and value of information technologies, which have become an integral part of human life in today’s world, is the information itself rather than technology, and it should be kept in mind that information technologies can only function as a means or tool in this knowledge-based social, economic, and cultural life. In other words, the determinant of the benefits, meaning, and importance of information technologies might be the conditions created by organizational factors such as cultural environment and organizational structure where knowledge is created, developed, and used and human resources have become the most important capital element and source of wealth.
The author declares no conflict of interest.
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