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Acute Kidney Injury.Pdf Pharmacology & Therapeutics 200 (2019) 1–12 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Acute kidney injury overview: From basic findings to new prevention and therapy strategies Sabrina Ribeiro Gonsalez a, Aline Leal Cortês a, Raquel Costa da Silva a, Jennifer Lowe b, Minolfa C. Prieto c, Lucienne da Silva Lara a,⁎ a Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho 373, Bloco J, sala 26, Rio de Janeiro, RJ 21941-902, Brazil b Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho 373, sala I2-035, Rio de Janeiro, RJ 21941-902, Brazil c Department of Physiology & Tulane Renal and Hypertension Center of Excellence, School of Medicine, Tulane University, New Orleans, LA 70112, USA article info abstract Keywords: Acute kidney injury Acute kidney injury (AKI) is defined as a decrease in kidney function within hours, which encompasses both in- Ischemia jury and impairment of renal function. AKI is not considered a pathological condition of single organ failure, but a Reperfusion syndrome in which the kidney plays an active role in the progression of multi-organ dysfunction. The incidence Renal physiology rate of AKI is increasing and becoming a common (8–16% of hospital admissions) and serious disease (four-fold increased hospital mortality) affecting public health costs worldwide. AKI also affects the young and previously healthy individuals affected by infectious diseases in Latin America. Because of the multifactorial pathophysiolog- ical mechanisms, there is no effective pharmacological therapy that prevents the evolution or reverses the injury once established; therefore, renal replacement therapy is the only current alternative available for renal patients. The awareness of an accurate and prompt recognition of AKI underlying the various clinical phenotypes is an ur- gent need for more effective therapeutic interventions to diminish mortality and socio-economic impacts of AKI. The use of biomarkers as an indicator of the initial stage of the disease is critical and the cornerstone to fulfill the gaps in the field. This review discusses emerging strategies from basic science toward the anticipation of features, treatment of AKI, and new treatments using pharmacological and stem cell therapies. We will also highlight bioartificial kidney studies, addressing the limitations of the development of this innovative technology. © 2019 Elsevier Inc. All rights reserved. Contents 1. Introduction................................................ 2 2. Acutekidneyinjury............................................ 2 3. Clinicalpresentation............................................ 5 4. CharacterizationofAKIbiomarkers..................................... 5 5. WhatistheavailablepharmacologicalarsenaltotreatAKI?.......................... 6 6. NewstrategiesofAKItreatmentandprevention............................... 7 7. Is the bioartificialkidneyapplicabletotreatAKI?............................... 8 8. Potential limitations of the current studies in the AKI field:whywestillfaceproblemswithAKI?......... 9 Abbreviations: AKD, Acute kidney disease; AKI, Acute kidney injury; Ang II, Angiotensin II; ATN, Acute tubular necrosis; ATP, Adenosine triphosphate; BAK, Bioartificial kidney; CBP, Pediatrics cardiopulmonary bypass; CKDu, Chronic kidney disease of unknown etiology; EM, Epithelial/mesenchymal; ER, Endoplasmic reticulum; ESRD, End stage of renal disease; EVs, Extracellular vesicles; GFR, Glomerular filtration rates; HSCs, Hematopoietic stem cells.; IGF7BP7, Insulin-like growth factor-binding protein; IPC, Ischemic pre-conditioning; iPSCs, Induced pluripotent stem cells; IRI, Ischemia-reperfusion injury; KIM-1, Kidney injury molecule-1; L-FABP, L-Type fatty acid binding protein; lcn2, Lipocalin 2; LC/MS, Liquid chromatography-mass spectrometry.; L-FABP, L-Type fatty acid binding protein; LOS, Length of stay; MALDI, Matrix-assisted laser desorption ionization imaging mass spectrometry; MAO, Monoamine oxidase; MMPs, Matrix metalloproteinases; MS, Mass spectrometry; MSCs, Mesenchymal stem cells.; NGAL, Neutrophil gelatinase-associated lipocalin; NMR, Nuclear magnetic resonance; NO, Nitric oxide; OHCA, Out-of-hospital cardiac arrest.; PD, Peritoneal dialysis; pmp, Per million population; POC, Ischemic post-conditioning; PTECs, Proximal tubule epithelial cells; rIPC, Remote ischemic preconditioning; ROS, Reactive oxygen species; RRT, Renal replacement therapy; sCR, Increase in serum creatinine; SELDI, Surface-enhanced laser desorption/ionization; SSCs, Spermatogonial stem cells; TIMP2, Tissue inhibitor of metalloproteinases 2; TGFβ, Transforming growth factor beta; VEGF, Vascular endothelium growth factor. ⁎ Corresponding author. E-mail address: [email protected] (L. Silva Lara). https://doi.org/10.1016/j.pharmthera.2019.04.001 0163-7258/© 2019 Elsevier Inc. All rights reserved. 2 S.R. Gonsalez et al. / Pharmacology & Therapeutics 200 (2019) 1–12 9. Conclusion.................................................9 Conflictofintereststatement...........................................9 Acknowledgments................................................9 References...................................................9 1. Introduction 1993). In the early 20th century, the term acute renal failure character- ized the reduction in urine volume. Recent multicenter observational co- Acute kidney injury (AKI) is characterized by the reduction of renal horts and administrative database have improved the understanding of function during a short period of time, on the order of days or weeks. the overall disease. Because of that the term “acute renal failure” was The renal alterations include a decrease in glomerular filtration rate – preferentially referred to as AKI, which encompasses both structural leading to an increase in serum concentration of urea nitrogen and damage and loss of renal function. The long period of time involving creatinine – and proteinuria (Hoste et al., 2018). In general, AKI is the first descriptions, the knowledge of the consequences of the acute associated with decreased renal perfusion pressure, major surgery, reduced urine volume and the criteria to characterize the insult delayed radiocontrast exposure, and pharmacological treatments (Basile, the development of a consensus standard definition. A survey in 2002 Anderson, & Sutton, 2012). The incidence of hospital-acquired AKI in revealed at least 35 definitions in the literature (Kellum, Levin, the United States is approximately 8 per 1000 admissions and up to Bouman, & Lameire, 2002). 20% in the intensive care unit (Kam-Tao-Li, Burdman, & Mehta, 2013). Several consensus definitions of AKI have been developed based ex- These patients presented more severe outcomes than patients with clusively on the serum creatinine and urine output and are also used in community-acquired AKI (Makris & Spanou, 2016). epidemiologic studies to identify the patients. The most used criteria are The incidence of AKI is increasing worldwide and is associated with The Kidney Disease: Improving Global Outcomes (KDIGO), Risk Injury high medical expenses during the post-AKI course and increased risk of Failure Loss End stage kidney disease (RIFLE) and the Acute Kidney In- developing an incapacitating chronic kidney disease along with a need jury Network (AKIN) (Gameiro, Fonseca, Jorge, & Lopes, 2018). The for renal replacement therapy (RRT). The outcome for the survivors is KDIGO guideline is based on the previous two classifications, unifying early retirement because of work disability. For example, the incremen- the AKI definition. In this classification, AKI is determined by an absolute tal cost of AKI in Canada is estimated to be over $200 million Canadian increase in serum creatinine (sCr), at least 0.3 mg/dL within 48 h, by a dollars per year (Collister et al., 2017). The costs related to AKI were 50% increase in sCr from baseline in 7 days, or a urine volume of determined by Silver and Chertow (2017) based on the data from the b0.5 mL/kg/h for at least 6 h. The small changes in sCr and/or urine out- National Inpatient Sample (NIS, the largest all-payer inpatient care data- put, as it occurs in mild kidney injury, can be a predictor of serious clin- base in the United States, containing over seven million hospitalizations ical consequences. Thus, the use of novel biomarkers is likely necessary from 95% of the United States population). AKI was associated with an to improve the AKI definition and mainly to help in diagnosis. increase in hospitalization costs of about $8000 (~$1800 per patient After 7 days, if the parameters proposed by KDIGO are still altered, and hospital characteristics) and an increase in about 3 days in the this establishes a critical period of vulnerability for renal patients. length of stay (LOS). Those numbers can be worse if AKI required dialy- When this condition persists for N90 days, it will be considered a chronic sis – about $42,000 per patient and 11 days of hospitalization (Silver & kidney disease (CKD). The term acute kidney disease (AKD) was pro- Chertow, 2017). In Brazil, as in the rest of Latin America, AKI has a bi- posed to define the period between 7 and 90 days where the patho- modal pattern: in urban areas, AKI is predominantly hospital-acquired physiological processes are ongoing. This period is essential to as in high-income countries, and in the poorer peripheral areas AKI af- introduce pharmacological
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