Megalin in acute kidney injury: foe and friend

2014 ◽  
Vol 306 (2) ◽  
pp. F147-F154 ◽  
Author(s):  
Ravikiran Mahadevappa ◽  
Rikke Nielsen ◽  
Erik Ilsø Christensen ◽  
Henrik Birn
Keyword(s):  
Acute Kidney Injury ◽  
Animal Models ◽  
Proximal Tubule ◽  
Essential Role ◽  
Kidney Injury ◽  
Current Evidence ◽  
Renal Protection ◽  
Tubule Cell ◽  
Cellular Protection ◽  
And Function

The kidney proximal tubule is a key target in many forms of acute kidney injury (AKI). The multiligand receptor megalin is responsible for the normal proximal tubule uptake of filtered molecules, including nephrotoxins, cytokines, and markers of AKI. By mediating the uptake of nephrotoxins, megalin plays an essential role in the development of some types of AKI. However, megalin also mediates the tubular uptake of molecules implicated in the protection against AKI, and changes in megalin expression have been demonstrated in AKI in animal models. Thus, modulation of megalin expression in response to AKI may be an important part of the tubule cell adaption to cellular protection and regeneration and should be further investigated as a potential target of intervention. This review explores current evidence linking megalin expression and function to the development, diagnosis, and progression of AKI as well as renal protection against AKI.

scholarly journals Cell profiling of mouse acute kidney injury reveals conserved cellular responses to injury

2020 ◽  
Vol 117 (27) ◽  
pp. 15874-15883 ◽  
Author(s):  
Yuhei Kirita ◽  
Haojia Wu ◽  
Kohei Uchimura ◽  
Parker C. Wilson ◽  
Benjamin D. Humphreys
Keyword(s):  
Acute Kidney Injury ◽  
Proximal Tubule ◽  
Communication Networks ◽  
Rat Kidney ◽  
Kidney Injury ◽  
Human Kidney ◽  
Cellular Responses ◽  
Acute Injury ◽  
Proximal Tubule Cell ◽  
Tubule Cell

After acute kidney injury (AKI), patients either recover or alternatively develop fibrosis and chronic kidney disease. Interactions between injured epithelia, stroma, and inflammatory cells determine whether kidneys repair or undergo fibrosis, but the molecular events that drive these processes are poorly understood. Here, we use single nucleus RNA sequencing of a mouse model of AKI to characterize cell states during repair from acute injury. We identify a distinct proinflammatory and profibrotic proximal tubule cell state that fails to repair. Deconvolution of bulk RNA-seq datasets indicates that this failed-repair proximal tubule cell (FR-PTC) state can be detected in other models of kidney injury, increasing during aging in rat kidney and over time in human kidney allografts. We also describe dynamic intercellular communication networks and discern transcriptional pathways driving successful vs. failed repair. Our study provides a detailed description of cellular responses after injury and suggests that the FR-PTC state may represent a therapeutic target to improve repair.

scholarly journals Cell profiling of mouse acute kidney injury reveals conserved cellular responses to injury

2020 ◽  
Author(s):  
Yuhei Kirita ◽  
Haojia Wu ◽  
Kohei Uchimura ◽  
Parker C. Wilson ◽  
Benjamin D. Humphreys
Keyword(s):  
Acute Kidney Injury ◽  
Proximal Tubule ◽  
Rna Sequencing ◽  
Therapeutic Target ◽  
Kidney Injury ◽  
Cellular Responses ◽  
Acute Injury ◽  
Proximal Tubule Cell ◽  
Tubule Cell ◽  
Single Nucleus

AbstractAfter acute kidney injury (AKI), patients either recover or alternatively develop fibrosis and chronic kidney disease. Interactions between injured epithelia, stroma and inflammatory cells determine whether kidneys repair or undergo fibrosis, but the molecular events that drive these processes are poorly understood. Here, we use single nucleus RNA sequencing of a mouse model of AKI to characterize cell states during repair from acute injury. We identify a distinct proinflammatory and profibrotic proximal tubule cell state that fails to repair. Deconvolution of bulk RNA-seq datasets indicates that this “failed-repair proximal tubule cell” or FR-PTC, state can be detected in other models of kidney injury, increasing in the aging rat kidney and over time in human kidney allografts. We also describe dynamic intercellular communication networks and discern transcriptional pathways driving successful vs. failed repair. Our study provides a detailed description of cellular responses after injury and suggests that the FR-PTC state may represent a therapeutic target to improve repair.Significance StatementSingle nucleus RNA sequencing revealed gene expression changes during repair after acute kidney injury. We describe a small population of proximal tubule cells that fail to repair (FR-PTC). Since this subpopulation expresses abundant pro-inflammatory and profibrotic genes, it may represent a new therapeutic target to improve repair and reduce fibrosis after AKI.

scholarly journals A1 adenosine receptor allosteric enhancer PD-81723 protects against renal ischemia-reperfusion injury

2012 ◽  
Vol 303 (5) ◽  
pp. F721-F732 ◽  
Author(s):  
Sang Won Park ◽  
Joo Yun Kim ◽  
Ahrom Ham ◽  
Kevin M. Brown ◽  
Mihwa Kim ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Side Effects ◽  
Proximal Tubule ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Wild Type ◽  
Renal Protection ◽  
Ischemic Acute Kidney Injury ◽  
Renal Tubular ◽  
Deficient Mice

Activation of A1 adenosine receptors (ARs) protects against renal ischemia-reperfusion (I/R) injury by reducing necrosis, apoptosis, and inflammation. However, extrarenal side effects (bradycardia, hypotension, and sedation) may limit A1AR agonist therapy for ischemic acute kidney injury. Here, we hypothesized that an allosteric enhancer for A1AR (PD-81723) protects against renal I/R injury without the undesirable side effects of systemic A1AR activation by potentiating the cytoprotective effects of renal adenosine generated locally by ischemia. Pretreatment with PD-81723 produced dose-dependent protection against renal I/R injury in A1AR wild-type mice but not in A1AR-deficient mice. Significant reductions in renal tubular necrosis, neutrophil infiltration, and inflammation as well as tubular apoptosis were observed in A1AR wild-type mice treated with PD-81723. Furthermore, PD-81723 decreased apoptotic cell death in human proximal tubule (HK-2) cells in culture, which was attenuated by a specific A1AR antagonist (8-cyclopentyl-1,3-dipropylxanthine). Mechanistically, PD-81723 induced sphingosine kinase (SK)1 mRNA and protein expression in HK-2 cells and in the mouse kidney. Supporting a critical role of SK1 in A1AR allosteric enhancer-mediated renal protection against renal I/R injury, PD-81723 failed to protect SK1-deficient mice against renal I/R injury. Finally, proximal tubule sphingosine-1-phosphate type 1 receptors (S1P1Rs) are critical for PD-81723-induced renal protection, as mice selectively deficient in renal proximal tubule S1P1Rs (S1P1Rflox/flox PEPCKCre/− mice) were not protected against renal I/R injury with PD-81723 treatment. Taken together, our experiments demonstrate potent renal protection with PD-81723 against I/R injury by reducing necrosis, inflammation, and apoptosis through the induction of renal tubular SK1 and activation of proximal tubule S1P1Rs. Our findings imply that selectively enhancing A1AR activation by locally produced renal adenosine may be a clinically useful therapeutic option to attenuate ischemic acute kidney injury without systemic side effects.

scholarly journals Determinants of Outcomes of Acute Kidney Injury: Clinical Predictors and Beyond

2021 ◽  
Vol 10 (6) ◽  
pp. 1175
Author(s):  
Emaad M. Abdel-Rahman ◽  
Faruk Turgut ◽  
Jitendra K. Gautam ◽  
Samir C. Gautam
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Kidney Injury ◽  
Complete Recovery ◽  
Severe Form ◽  
Clinical Syndrome ◽  
Current Evidence ◽  
Clinical Predictors ◽  
End Stage

Acute kidney injury (AKI) is a common clinical syndrome characterized by rapid impairment of kidney function. The incidence of AKI and its severe form AKI requiring dialysis (AKI-D) has been increasing over the years. AKI etiology may be multifactorial and is substantially associated with increased morbidity and mortality. The outcome of AKI-D can vary from partial or complete recovery to transitioning to chronic kidney disease, end stage kidney disease, or even death. Predicting outcomes of patients with AKI is crucial as it may allow clinicians to guide policy regarding adequate management of this problem and offer the best long-term options to their patients in advance. In this manuscript, we will review the current evidence regarding the determinants of AKI outcomes, focusing on AKI-D.

scholarly journals Insulin-like growth factor binding protein 7 and tissue inhibitor of metalloproteinases-2: differential expression and secretion in human kidney tubule cells

2017 ◽  
Vol 312 (2) ◽  
pp. F284-F296 ◽  
Author(s):  
David R. Emlet ◽  
Nuria Pastor-Soler ◽  
Allison Marciszyn ◽  
Xiaoyan Wen ◽  
Hernando Gomez ◽  
...  
Keyword(s):  
Cell Culture ◽  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Human Kidney ◽  
Distal Tubule ◽  
Cell Types ◽  
Tissue Inhibitor Of Metalloproteinases ◽  
Tubule Cell ◽  
Tubule Cells

We have characterized the expression and secretion of the acute kidney injury (AKI) biomarkers insulin-like growth factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2) in human kidney epithelial cells in primary cell culture and tissue. We established cell culture model systems of primary kidney cells of proximal and distal tubule origin and observed that both proteins are indeed expressed and secreted in both tubule cell types in vitro. However, TIMP-2 is both expressed and secreted preferentially by cells of distal tubule origin, while IGFBP7 is equally expressed across tubule cell types yet preferentially secreted by cells of proximal tubule origin. In human kidney tissue, strong staining of IGFBP7 was seen in the luminal brush-border region of a subset of proximal tubule cells, and TIMP-2 stained intracellularly in distal tubules. Additionally, while some tubular colocalization of both biomarkers was identified with the injury markers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, both biomarkers could also be seen alone, suggesting the possibility for differential mechanistic and/or temporal profiles of regulation of these early AKI biomarkers from known markers of injury. Last, an in vitro model of ischemia-reperfusion demonstrated enhancement of secretion of both markers early after reperfusion. This work provides a rationale for further investigation of these markers for their potential role in the pathogenesis of acute kidney injury.

scholarly journals Acute Kidney Injury Recognition and Management: A Review of the Literature and Current Evidence

2015 ◽  
Vol 8 (5) ◽  
pp. 120 ◽  
Author(s):  
Syed Raza Shah ◽  
Sameer Altaf Tunio ◽  
Mohammad Hussham Arshad ◽  
Zorays Moazzam ◽  
Komal Noorani ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Damage Control ◽  
Kidney Injury ◽  
Control Measures ◽  
Current Evidence ◽  
Disease Treatment ◽  
Complex Disorder ◽  
Electrolyte Homeostasis ◽  
Life Threatening ◽  
Life Threatening Event

<p>Acute renal failure is defined as a rapid decrease in the glomerular filtration rate, occurring over a period of hours to days and by the inability of the kidney to regulate fluid and electrolyte homeostasis appropriately. AKI is a catastrophic, life-threatening event in critically ill patients. AKI can be divided into pre-renal injury, intrinsic kidney disease (including vascular insults) and obstructive uropathies. The prognosis of AKI is highly dependent on the underlying cause of the injury. Children who have AKI as a component of multisystem failure have a much higher mortality rate than children with intrinsic renal disease. Treatment of AKI is subjected to risk stratification and ongoing damage control measures, such as patients with sepsis, exposure to nephrotoxic agents, ischemia, bloody diarrhea, or volume loss, could be helped by optimizing the fluid administrations, antibiotics possessing least nephrotoxic potential, blood transfusion where hemoglobin is dangerously low, limiting the use of nephrotoxic agents including radio contrast use, while maximize the nutrition. Acute kidney injury remains a complex disorder with an apparent differentiation in pathology between septic and nonseptic forms of the disease. Although more studies are still required, progress in this area has been steady over the last decade with purposeful international collaboration.</p>

scholarly journals Cost-effectiveness and value of information analysis of NephroCheck and NGAL tests compared to standard care for the diagnosis of acute kidney injury

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Elisabet Jacobsen ◽  
Simon Sawhney ◽  
Miriam Brazzelli ◽  
Lorna Aucott ◽  
Graham Scotland ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cost Effectiveness ◽  
Diagnostic Accuracy ◽  
Value Of Information ◽  
Standard Care ◽  
Kidney Injury ◽  
Current Evidence ◽  
Future Research ◽  
Test Accuracy ◽  
Decision Uncertainty

Abstract Background Early and accurate acute kidney injury (AKI) detection may improve patient outcomes and reduce health service costs. This study evaluates the diagnostic accuracy and cost-effectiveness of NephroCheck and NGAL (urine and plasma) biomarker tests used alongside standard care, compared with standard care to detect AKI in hospitalised UK adults. Methods A 90-day decision tree and lifetime Markov cohort model predicted costs, quality adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) from a UK NHS perspective. Test accuracy was informed by a meta-analysis of diagnostic accuracy studies. Clinical trial and observational data informed the link between AKI and health outcomes, health state probabilities, costs and utilities. Value of information (VOI) analysis informed future research priorities. Results Under base case assumptions, the biomarker tests were not cost-effective with ICERs of £105,965 (NephroCheck), £539,041 (NGAL urine BioPorto), £633,846 (NGAL plasma BioPorto) and £725,061 (NGAL urine ARCHITECT) per QALY gained compared to standard care. Results were uncertain, due to limited trial data, with probabilities of cost-effectiveness at £20,000 per QALY ranging from 0 to 99% and 0 to 56% for NephroCheck and NGAL tests respectively. The expected value of perfect information (EVPI) was £66 M, which demonstrated that additional research to resolve decision uncertainty is worthwhile. Conclusions Current evidence is inadequate to support the cost-effectiveness of general use of biomarker tests. Future research evaluating the clinical and cost-effectiveness of test guided implementation of protective care bundles is necessary. Improving the evidence base around the impact of tests on AKI staging, and of AKI staging on clinical outcomes would have the greatest impact on reducing decision uncertainty.

Abstract 655: Ischemia-induced Epoxyeicosatrienoic Acid Release Protects Female Rats From Acute Kidney Injury

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Duska Dragun ◽  
Uwe Hoff ◽  
Maximilian Blum ◽  
Gordana Bubalo ◽  
Mandy Fechner ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Creatinine Clearance ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Female Rats ◽  
Epoxyeicosatrienoic Acid ◽  
Renal Protection ◽  
Sham Control ◽  
Male And Female ◽  
Enhanced Production

Females are naturally protected against ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) in various clinical and experimental settings. However, the underlying mechanisms are unknown. We hypothesized that female protection may be conferred by enhanced production of cytochrome P450 (CYP)-dependent epoxyeicosatrienoic acids (EETs) that promote vasodilation as well as antiinflammatory and antiapoptotic pathways in the kidney. To test this hypothesis, we first analyzed the renal CYP-eicosanoid profile by liquid chromatography tandem mass spectrometry in male and female Lewis rats. Ischemia was induced through 45 min of left renal vessel clamping after right nephrectomy (n=6-8 per group). In non-ischemic controls, male and female kidneys stored almost identical amounts of EETs as well as 20-hydroxyeicosatetraenoic acid (20-HETE), both predominantly esterified into phospholipids, under basal non-ischemic conditions. 45 min of ischemia induced a massive release of EETs from membrane stores in females but not males. The free renal EET-levels reached 70.2±20.1 in females compared to only 4.6±1.3 ng/g in males. After ischemia, the ratio of free EETs to free 20-HETE was about 1:1 in females and 1:3 in males. Next, we proved the functional importance of EETs in renal protection by pretreating males with a synthetic EET-agonist (12-HUDE) and females with a selective EET-antagonist (14,15-EEZE-mSI). As analyzed two days after reperfusion, the EET-agonist protected males against loss of creatinine clearance (1.03±0.18 vs. 0.26±0.02 ml/min, p<0.01 vs. vehicle, compared to 1.28±0.06 ml/min in sham control). Females were rendered susceptible to I/R-injury by the EET-antagonist (creatinine clearance: 0.25±0.05 vs. 0.67±0.04; p<0.01 vs. vehicle, compared to 0.81±0.04 ml/min in sham control). Changes in inflammatory cell infiltration and tubular apoptosis paralleled these effects on renal function. Our results indicate that female rats are protected against renal I/R-injury by enhanced ischemia-induced EET-release and demonstrate that renal protection can be transferred to males using synthetic EET-agonists.

Acute Kidney Injury following Cardiac Surgery

2015 ◽  
pp. 451-480
Author(s):  
Bryan Romito ◽  
Joseph Meltzer
Keyword(s):  
Acute Kidney Injury ◽  
Cardiac Surgery ◽  
Surgical Techniques ◽  
Kidney Injury ◽  
Renal Physiology ◽  
General Management ◽  
Novel Biomarkers ◽  
Short And Long Term ◽  
And Function

The primary goal of this chapter is to provide the reader with an overview of basic renal physiology and function and to review the identification, pathogenesis, and treatment of acute kidney injury following cardiac surgery. Particular focus will be directed toward the diagnostic criteria for acute kidney injury, short- and long-term impacts on patient outcomes, role of novel biomarkers, mechanisms of acute renal injury, general management principles, preventative strategies, and the influence of anesthetic and surgical techniques on its development. The content of this chapter will serve to underscore a particularly harmful but likely underappreciated problem affecting patients in the cardiothoracic critical care setting.

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