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      The Potential of Alkaline Phosphatase as a Treatment for Sepsis-Associated Acute Kidney Injury

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          Sepsis-associated acute kidney injury (AKI) is associated with a high attributable mortality and an increased risk of developing chronic kidney failure in survivors. As a successful therapy is, as yet, unavailable, a pharmacological treatment option is clearly warranted. Recently, two small phase II clinical trials demonstrated beneficial renal effects of bovine-derived alkaline phosphatase administration in critically ill patients with sepsis-associated AKI. The rationale behind the renal protective effects remains to be fully elucidated, but is likely to be related to dephosphorylation and thereby detoxification of detrimental molecules involved in the pathogenesis of sepsis-associated AKI. A potent candidate target molecule might be endotoxin (lipopolysaccharide) from the cell wall of Gram-negative bacteria, which is associated with the development of sepsis and becomes nontoxic after being dephosphorylated by alkaline phosphatase. Another target of alkaline phosphatase could be adenosine triphosphate, a proinflammatory mediator released during cellular stress, which can be converted by alkaline phosphatase into the tissue-protective and anti-inflammatory molecule adenosine. Human recombinant alkaline phosphatase, a recently developed replacement for bovine-derived alkaline phosphatase, has shown promising results in the preclinical phase. As its safety and tolerability were recently confirmed in a phase I clinical trial, the renal protective effect of human recombinant alkaline phosphatase in sepsis-associated AKI shall be investigated in a multicenter phase II clinical trial starting at the end of this year.

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          Adenosine 5'-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation.

          Human health is under constant threat of a wide variety of dangers, both self and nonself. The immune system is occupied with protecting the host against such dangers in order to preserve human health. For that purpose, the immune system is equipped with a diverse array of both cellular and non-cellular effectors that are in continuous communication with each other. The naturally occurring nucleotide adenosine 5'-triphosphate (ATP) and its metabolite adenosine (Ado) probably constitute an intrinsic part of this extensive immunological network through purinergic signaling by their cognate receptors, which are widely expressed throughout the body. This review provides a thorough overview of the effects of ATP and Ado on major immune cell types. The overwhelming evidence indicates that ATP and Ado are important endogenous signaling molecules in immunity and inflammation. Although the role of ATP and Ado during the course of inflammatory and immune responses in vivo appears to be extremely complex, we propose that their immunological role is both interdependent and multifaceted, meaning that the nature of their effects may shift from immunostimulatory to immunoregulatory or vice versa depending on extracellular concentrations as well as on expression patterns of purinergic receptors and ecto-enzymes. Purinergic signaling thus contributes to the fine-tuning of inflammatory and immune responses in such a way that the danger to the host is eliminated efficiently with minimal damage to healthy tissues.
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            A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury.

            Given that the leading clinical conditions associated with acute kidney injury (AKI), namely, sepsis, major surgery, heart failure, and hypovolemia, are all associated with shock, it is tempting to attribute all AKI to ischemia on the basis of macrohemodynamic changes. However, an increasing body of evidence has suggested that in many patients, AKI can occur in the absence of overt signs of global renal hypoperfusion. Indeed, sepsis-induced AKI can occur in the setting of normal or even increased renal blood flow. Accordingly, renal injury may not be entirely explained solely on the basis of the classic paradigm of hypoperfusion, and thus other mechanisms must come into play. Herein, we put forward a "unifying theory" to explain the interplay between inflammation and oxidative stress, microvascular dysfunction, and the adaptive response of the tubular epithelial cell to the septic insult. We propose that this response is mostly adaptive in origin, that it is driven by mitochondria, and that it ultimately results in and explains the clinical phenotype of sepsis-induced AKI.
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              Acute renal failure in patients with severe sepsis and septic shock--a significant independent risk factor for mortality: results from the German Prevalence Study.

              Sound data about the prevalence of acute renal failure (ARF) among patients with severe sepsis and septic shock are lacking. Further, it is not known whether ARF is an independent risk factor for mortality in septic patients or merely an indicator of disease severity. A prospective cross-sectional one-day prevalence study was carried out in a representative sample of German ICUs, divided into five strata ( 600 beds; university hospitals). 3877 patients were screened of whom 415 had severe sepsis and septic shock. Fourteen patients (3.4%) had chronic dialysis-dependent RF and were excluded from analysis. Of the remaining 401 patients, 166 (41.4%) had ARF, as defined by a rise in creatinine above twice the upper limit of normal and/or a drop in urine output to < 0.5 ml/kg bodyweight. Median APACHE II score was 22 in patients with ARF and 16 in patients without ARF (p< 0.0001). Patients with severe sepsis/septic shock had an overall hospital mortality of 55.2%. Hospital mortality in patients with ARF was 67.3% and without ARF 42.8% (p< 0.0001). After adjustment for APACHE II score and age, ARF remained a significant independent risk factor for death [odds ratio (OR) 2.11, 95% confidence interval (CI) 1.27-3.52]. Mortality in septic patients was not associated with pre-existing, non-dialysis-dependent chronic kidney disease, whereas in dialysis-dependent patients with sepsis mortality increased to 86%. In this representative survey in patients with severe sepsis/septic shock, prevalence of ARF is high with 41.4%. ARF represents a significant independent risk factor for mortality in these patients.

                Author and article information

                Nephron Clin Pract
                Nephron Clinical Practice
                S. Karger AG
                September 2014
                24 September 2014
                : 127
                : 1-4
                : 144-148
                Departments of aIntensive Care Medicine and bPharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands
                Author notes
                *P. Pickkers, Department of Intensive Care Medicine, Radboud University Medical Center, PO Box 9101, Internal Mailbox 710, NL-6500 HB Nijmegen (The Netherlands), E-Mail
                363256 Nephron Clin Pract 2014;127:144-148
                © 2014 S. Karger AG, Basel

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                Page count
                Figures: 1, Pages: 5
                Original Paper


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