Various biomarkers of acute kidney injury (AKI) have been discovered and characterized in the recent past. These molecules can be detected in urine or blood and signify structural damage to the kidney. Clinically, they are proposed as adjunct diagnostics to serum creatinine and urinary output to improve the early detection, differential diagnosis and prognostic assessment of AKI. The most obvious requirements for a biomarker include its reflection of the underlying pathophysiology of the disease. Hence, a biomarker of AKI should derive from the injured kidney and reflect a molecular process intimately connected with tissue injury. Here, we provide an overview of the basic pathophysiology, the cellular sources and the clinical performance of the most important currently proposed biomarkers of AKI: neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), interleukin-18 (IL-18), insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinase 2 (TIMP-2) and calprotectin (S100A8/9). We also acknowledge each biomarker's advantages and disadvantages as well as important knowledge gaps and perspectives for future studies.

/pdf/biomarkers-in-acute-kidney-injury-pathophysiological-basis-jjii3a30z1.pdf

Biomarkers in acute kidney injury – pathophysiological basis and clinical performance

Renal inflammation is a universal response to infectious and noninfectious triggers. Sensors of the innate immune system, such as Toll-like receptors or RIG-like receptors, provide danger recognition platforms on renal cells that integrate and translate the diverse triggers of renal inflammation by inducing cell activation and the secretion of proinflammatory cytokines and chemokines. As a new entry, the inflammasome-forming NLR genes integrate various danger signals into caspase-1-activating platforms that regulate the processing and secretion of pro-IL-1β and pro-IL-18 into the mature and active cytokines. Accumulating data now document a role for the NLRP3 inflammasome and IL-1β/IL-18 in many diseases, including atherosclerosis, diabetes, amyloidosis, malaria, crystal-related diseases, and other autoinflammatory disorders, identifying this innate immune pathway as an attractive therapeutic target. Here we review the current knowledge regarding inflammasome signaling and outline existing evidence on the expression and functional role of the inflammasome-caspase-1-IL-1β/IL-18 axis in kidney disease. We further provide a perspective on the potential roles of the inflammasomes in the pathogenesis of acute and chronic kidney diseases.

/pdf/the-inflammasomes-in-kidney-disease-19d2lbluri.pdf

The Inflammasomes in Kidney Disease

Acute kidney injury (AKI) is a common complication of critical illnesses and has a significant impact on outcomes, including mortality and morbidities. Unfortunately, apart from prophylactic measures, no effective treatment for this syndrome is known. Therefore, early recognition of AKI not only can provide better opportunities for preventive interventions, but also opens many gates for research and development of effective therapeutic options. Over the last few years, several new AKI biomarkers have been discovered and validated to improve early detection, differential diagnosis, and differentiation of patients into risk groups for progressive renal failure, need for renal replacement therapy (RRT), or death. These novel AKI biomarkers complement serum creatinine (SCr) and urine output, which are the standard diagnostic tools for AKI detection. In this article, we review the available literature on characteristics of promising AKI biomarkers that are currently the focus of preclinical and clinical investigations. These biomarkers include neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), liver-type fatty acid-binding protein, interleukin 18 (lL-18), insulin-like growth factor-binding protein 7, tissue inhibitor of metalloproteinase 2 (TIMP-2), calprotectin, urine angiotensinogen (AGT), and urine microRNA. We then describe the clinical performance of these biomarkers for diagnosis and prognostication. We also appraise each AKI biomarker's advantages and limitations as a tool for early AKI recognition and prediction of clinical outcomes after AKI. Finally, we review the current and future states of implementation of biomarkers in the clinical practice.

https://www.degruyter.com/downloadpdf/j/cclm.2017.55.issue-8/cclm-2016-0973/cclm-2016-0973.xml

Biomarkers of acute kidney injury: the pathway from discovery to clinical adoption.

Inflammasomes are multiprotein innate immune complexes that regulate caspase-dependent inflammation and cell death. Pattern recognition receptors, such as nucleotide-binding oligomerization domain (NOD)-like receptors and absent in melanoma 2 (AIM2)-like receptors, sense danger signals or cellular events to activate canonical inflammasomes, resulting in caspase 1 activation, pyroptosis and the secretion of IL-1β and IL-18. Non-canonical inflammasomes can be activated by intracellular lipopolysaccharides, toxins and some cell signalling pathways. These inflammasomes regulate the activation of alternative caspases (caspase 4, caspase 5, caspase 11 and caspase 8) that lead to pyroptosis, apoptosis and the regulation of other cellular pathways. Many inflammasome-related genes and proteins have been implicated in animal models of kidney disease. In particular, the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome has been shown to contribute to a wide range of acute and chronic microbial and non-microbial kidney diseases via canonical and non-canonical mechanisms that regulate inflammation, pyroptosis, apoptosis and fibrosis. In patients with chronic kidney disease, immunomodulation therapies targeting IL-1β such as canakinumab have been shown to prevent cardiovascular events. Moreover, findings in experimental models of kidney disease suggest that small-molecule inhibitors targeting NLRP3 and other inflammasome components are promising therapeutic agents. In this Review, the authors discuss the biology of canonical and non-canonical inflammasomes and inflammasome-forming genes in the kidney, including their different functions in the various kidney compartments and their potential as therapeutic targets.

The role of inflammasomes in kidney disease.

Introduction: The P2X7 receptor (P2X7R) has an important role in inflammation and immunity, but until recently, clinical application has been limited by a lack of specific antagonists. Recent studies using P2X7R knockout mice and specific receptor antagonists have shown that the P2X7R is an important therapeutic target in inflammatory diseases. Areas covered: We have reviewed the current literature on the role of the P2X7R in inflammatory diseases, focusing on potential therapeutic applications of selective P2X7R antagonists as anti-inflammatory agents. Particular emphasis has been placed on the potential role of P2X7R in common inflammatory diseases. The latest developments in Phase I and II clinical trials of P2X7R antagonists are covered. Expert opinion: Recent studies using gene knockout mice and selective P2X7R antagonists suggest that P2X7R is a viable therapeutic target for inflammatory diseases. However, efficacious P2X7R antagonists for use in clinical studies are still at an early stage of devel...

/pdf/a-potential-therapeutic-role-for-p2x7-receptor-p2x7r-2qyyynvseg.pdf

A potential therapeutic role for P2X7 receptor (P2X7R) antagonists in the treatment of inflammatory diseases

We determined the cellular location of interleukin-18 (IL-18) and caspase-1 and the purinergic receptor P2X7, two proteins necessary for its activation and secretion. The mRNA and protein of IL-18 were detectable in normal human kidney by means of polymerase chain reaction (PCR), in situ hybridization, and Western blot. Immunohistochemistry located IL-18 to nephron segments containing calbinbinD28k or aquaporin-2 that suggest location in the distal convoluted and the connecting tubule and to parts of the collecting duct. IL-18 was not detected in the thick ascending limb of Henle. Confocal microscopy showed that IL-18 was expressed in cells negative for calbindin-D28k and for aquaporin-2 but positive for the vacuolar H þ -ATPase. This demonstrates that the intercalated cells produce IL-18. These segments were also positive for caspase-1 and P2X7 that are essential for IL-18 secretion. Our results show that IL-18 is constitutively expressed by intercalated cells of the late distal convoluted tubule, the connecting tubule, and the collecting duct of the healthy human kidney. Since IL-18 is an early component of the inflammatory cytokine cascade, its location suggests that renal intercalated cells may contribute to immediate immune response of the kidney.

IL-18 is expressed in the intercalated cell of human

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IL-18 is expressed in the intercalated cell of human