scholarly journals Targeting acute kidney injury in COVID-19

2020 ◽  
Vol 35 (10) ◽  
pp. 1652-1662 ◽  
Author(s):  
John A Kellum ◽  
J W Olivier van Till ◽  
George Mulligan
Keyword(s):  
Acute Kidney Injury ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Perfusion ◽  
Endothelial Damage ◽  
Acid Oxidation ◽  
Acid Base ◽  
The Impact ◽  
Pathophysiologic Mechanisms

Abstract As of 15 August 2020, Coronavirus disease 2019 (COVID-19) has been reported in >21 million people world-wide and is responsible for more than 750,000 deaths. The occurrence of acute kidney injury (AKI) in patients hospitalized with COVID-19 has been reported to be as high as 43%. This is comparable to AKI in other forms of pneumonia requiring hospitalization, as well as in non-infectious conditions like cardiac surgery. The impact of AKI on COVID-19 outcomes is difficult to assess at present but, similar to other forms of sepsis, AKI is strongly associated with hospital mortality. Indeed, mortality is reported to be very low in COVID-19 patients without AKI. Given that AKI contributes to fluid and acid–base imbalances, compromises immune response and may impair resolution of inflammation, it seems likely that AKI contributes to mortality in these patients. The pathophysiologic mechanisms of AKI in COVID-19 are thought to be multifactorial including systemic immune and inflammatory responses induced by viral infection, systemic tissue hypoxia, reduced renal perfusion, endothelial damage and direct epithelial infection with Severe Acute Respiratory Syndrome Coronavirus 2. Mitochondria play a central role in the metabolic deregulation in the adaptive response to the systemic inflammation and are also found to be vital in response to both direct viral damage and tissue reperfusion. These stress conditions are associated with increased glycolysis and reduced fatty acid oxidation. Thus, there is a strong rationale to target AKI for therapy in COVID-19. Furthermore, many approaches that have been developed for other etiologies of AKI such as sepsis, inflammation and ischemia–reperfusion, have relevance in the treatment of COVID-19 AKI and could be rapidly pivoted to this new disease.

scholarly journals Role of Endothelial Prolyl-4-Hydroxylase Domain Protein/Hypoxia-Inducible Factor Axis in Acute Kidney Injury

Nephron ◽  
2021 ◽  
pp. 1-6
Author(s):  
Ratnakar Tiwari ◽  
Pinelopi P. Kapitsinou
Keyword(s):  
Acute Kidney Injury ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hypoxia Inducible Factor ◽  
Kidney Injury ◽  
Cell Types ◽  
Endothelial Damage ◽  
Adaptation To Hypoxia ◽  
Low Oxygen

Ischemia reperfusion injury (IRI) results from a cessation or restriction of blood supply to an organ followed by reestablishment of perfusion and reoxygenation. In the kidney, IRI due to transplantation, cardiac surgery with cardiopulmonary bypass, and other major vascular surgeries contributes to acute kidney injury (AKI), a clinical condition associated with significant morbidity and mortality in hospitalized patients. In the postischemic kidney, endothelial damage promotes inflammatory responses and leads to persistent hypoxia of the renal tubular epithelium. Like other cell types, endothelial cells respond to low oxygen tension by multiple hypoxic signaling mechanisms. Key mediators of adaptation to hypoxia are hypoxia-inducible factors (HIF)-1 and -2, transcription factors whose activity is negatively regulated by prolyl-hydroxylase domain proteins 1 to 3 (PHD1 to PHD3). The PHD/HIF axis controls several processes determining injury outcome, including ATP generation, cell survival, proliferation, and angiogenesis. Here, we discuss recent advances in our understanding of the endothelial-derived PHD/HIF signaling and its effects on postischemic AKI.

scholarly journals Acute kidney injury during pregnancy leads to increased sFlt-1 and sEng and decreased renal T regulatory cells in pregnant rats with HELLP syndrome

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jamie Szczepanski ◽  
Shauna-Kay Spencer ◽  
Ashley Griffin ◽  
Teylor Bowles ◽  
Jan Michael Williams ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Acute Kidney Injury ◽  
Hellp Syndrome ◽  
T Regulatory Cells ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Regulatory Cells ◽  
T Helper 17 ◽  
Pregnant Rats ◽  
The Impact

Abstract Background The incidence of acute kidney injury (AKI) during pregnancy precedes a high maternal mortality rate of 20–40%. AKI during pregnancy has multiple etiologies; however, the more common are maternal hypertensive disorders, which include preeclampsia and HELLP (hemolysis, elevated liver enzyme, low platelet) syndrome. Therefore, we sought to assess the impact of AKI on blood pressure, kidney injury, and anti-angiogenic factors during pregnancies with and without HELLP syndrome. Methods On gestational day (GD) 12, mini-osmotic pumps were inserted into a subset of normal pregnant (NP) rats infusing 4.7 μg/kg soluble fms-like tyrosine kinase-1 (sFlt-1) and 7 μg/kg soluble endoglin (sEng) to induce HELLP syndrome. On GD18, the renal pedicles were occluded for 45 min to induce AKI via bilateral ischemia reperfusion in a subset of NP (n = 18) or HELLP (n = 20) rats. Control NP (n = 20) and HELLP (n = 20) rats underwent a SHAM surgery on GD18. Plasma, urine, and maternal organs were saved for further analysis. Renal injury was assessed via renal histopathology, glomerular filtration rate (GFR), T cell infiltration, and assessment of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Data was measured via two-way analysis of variance with Tukey’s test for post hoc analysis. Results Blood pressures were increased in HELLP+AKI rats (p = 0.0001); both NP+AKI and HELLP+AKI rats had increased lactate dehydrogenase (p < 0.0001) and aspartate aminotransferase levels (p < 0.0001), and decreased platelet levels (p < 0.001) vs. NP rats. HELLP+AKI (p = 0.002) and HELLP rats (p = 0.0002) had evidence of renal fibrosis vs. NP rats. GFR was decreased in HELLP+AKI (p = 0.01) rats vs. NP rats. Urinary KIM-1 was increased in NP+AKI rats vs. NP (p = 0.003) and HELLP rats (p = 0.01). HELLP+AKI rats had increased urinary KIM-1 vs. NP (p = 0.0008) and HELLP rats (p = 0.004) and increased NGAL vs. HELLP rats (p = 0.002). HELLP+AKI rats had increased sFlt-1 (p = 0.009) vs. NP rats. NP+AKI (p = 0.02) and HELLP+AKI (p = 0.007) rats had increased sEng vs. NP rats. CD3+CD4+ T cells were significantly increased in HELLP+AKI rats vs. NP (p = 0.0002) and NP+AKI (p = 0.05) rats. T regulatory cells were significantly decreased in HELLP+AKI (p = 0.03) and NP+AKI (p = 0.02) rats vs. NP rats; there were no changes between groups in T helper 17 cells (p = 0.34). Conclusion The findings in this study suggest that AKI during pregnancy contributes to increased blood pressure and biochemical markers for HELLP syndrome, creates an anti-angiogenic imbalance, and exacerbates kidney injury as shown on histopathology, GFR, and kidney injury markers.

scholarly journals P0558DICLOFENAC ENHANCES RENAL INFLAMMATION IN EXPERIMENTAL SUBCLINICAL ACUTE KIDNEY INJURY (AKI)

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Johanna Störmer ◽  
Faikah Gueler ◽  
Song Rong ◽  
Mi-Sun Jang ◽  
Nelli Shushakova ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Oral Dose ◽  
Single Oral Dose ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Perfusion ◽  
Tubular Atrophy ◽  
Renal Inflammation ◽  
Urine Production

Abstract Background and Aims Diclofenac is frequently used for pain control. In a previous study, we showed that already a single oral dose of diclofenac could reduce renal perfusion in healthy individuals. To investigate the influence of oral diclofenac administration on renal inflammation in the setting of pre-existing renal damage, we used a mouse model of subclinical acute kidney injury (AKI) induced by renal ischemia-reperfusion injury (IRI) followed by diclofenac administration. Method Male CD1 mice (7-8 weeks old) underwent unilateral renal pedicle clamping for 15min to induce subclinical AKI. After reperfusion mice received a single oral dose of 100 or 200mg/kg diclofenac via oral gavage. Vehicle treated mice with unilateral IRI served as control. At day 1, mice were placed into metabolic cages to collect urine. Histology was performed on day 1 and 14 for renal morphology. Inflammation and fibrosis were investigated by immunohistochemistry and qPCR. Results Diclofenac treated mice showed reduced urine production. Morphologically, signs of AKI were more pronounced in diclofenac treated kidneys which also showed more Cox-2 positive tubuli in the cortex. On mRNA expression level the pro-inflammatory markers IL-6 and CXCL2, the chemoattractant for neutrophils, were elevated in the diclofenac group. Early upregulation of the pro-fibrotic markers CTGF and PAI-1 was detected already on d1 after IRI in the diclofenac group and tubular atrophy was pronounced after two weeks. Conclusion Already, a single oral dose of diclofenac causes aggravation of renal inflammation and progressive renal fibrosis in the setting of pre-existing subclinical acute kidney injury.

scholarly journals The p53 inhibitor pifithrin-α can stimulate fibrosis in a rat model of ischemic acute kidney injury

2012 ◽  
Vol 302 (2) ◽  
pp. F284-F291 ◽  
Author(s):  
Pierre C. Dagher ◽  
Erik M. Mai ◽  
Takashi Hato ◽  
So-Young Lee ◽  
Melissa D. Anderson ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Inflammatory Responses ◽  
Kidney Injury ◽  
Vehicle Control ◽  
Acute Administration ◽  
Protective Effects ◽  
Long Term Effects ◽  
Mesenchymal Transition ◽  
The Impact ◽  
Microvascular Rarefaction

Inhibition of the tumor suppressor p53 diminishes tubular cell apoptosis and protects renal function in animal models of acute kidney injury (AKI). Therefore, targeting p53 has become an attractive therapeutic strategy in the approach to AKI. Although the acute protective effects of p53 inhibition in AKI have been examined, there is still relatively little known regarding the impact of acute p53 inhibition on the chronic sequelae of AKI. Consequently, we utilized the p53 inhibitor pifithrin-α to examine the long-term effects of p53 inhibition in a rodent model of ischemic AKI. Male Sprague-Dawley rats were subjected to bilateral renal artery clamping for 30 min followed by reperfusion for up to 8 wk. Pifithrin-α or vehicle control was administered at the time of surgery and then daily for 2 days [brief acute administration (BA)] or 7 days [prolonged acute administration (PA)]. Despite the acute protective effect of pifithrin-α in models of ischemic AKI, we found no protection in the microvascular rarefaction at 4 wk or development fibrosis at 8 wk with pifithrin-α administered on the BA schedule compared with vehicle control-treated animals. Furthermore, pifithrin-α administered on a PA schedule actually produced worse fibrosis compared with vehicle control animals after ischemic injury [21%/area (SD4.4) vs.16%/area (SD3.6)] as well as under sham conditions [2.6%/area (SD1.8) vs. 4.7%/area (SD1.3)]. The development of fibrosis with PA administration was independent of microvascular rarefaction. We identified enhanced extracellular matrix production, epithelial-to-mesenchymal transition, and amplified inflammatory responses as potential contributors to the augmented fibrosis observed with PA administration of pifithrin-α.

scholarly journals Genetic Deletion of Vasohibin-2 Exacerbates Ischemia-Reperfusion-Induced Acute Kidney Injury

2020 ◽  
Vol 21 (12) ◽  
pp. 4545 ◽  
Author(s):  
Hiromasa Miyake ◽  
Katsuyuki Tanabe ◽  
Satoshi Tanimura ◽  
Yuri Nakashima ◽  
Tomoyo Morioka ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Diseases ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Neutrophil Infiltration ◽  
Endothelial Damage ◽  
Tubular Damage ◽  
Renal Tubules ◽  
Inflammatory Infiltration ◽  
Peritubular Capillaries

Acute kidney injury (AKI) has been increasingly recognized as a risk factor for transition to chronic kidney disease. Recent evidence suggests that endothelial damage in peritubular capillaries can accelerate the progression of renal injury. Vasohibin-2 (VASH2) is a novel proangiogenic factor that promotes tumor angiogenesis. However, the pathophysiological roles of VASH2 in kidney diseases remain unknown. In the present study, we examined the effects of VASH2 deficiency on the progression of ischemia–reperfusion (I/R) injury-induced AKI. I/R injury was induced by bilaterally clamping renal pedicles for 25 min in male wild-type (WT) and Vash2 homozygous knockout mice. Twenty-four hours later, I/R injury-induced renal dysfunction and tubular damage were more severe in VASH2-deficient mice than in WT mice, with more prominent neutrophil infiltration and peritubular capillary loss. After induction of I/R injury, VASH2 expression was markedly increased in injured renal tubules. These results suggest that VASH2 expression in renal tubular epithelial cells might be essential for alleviating I/R injury-induced AKI, probably through protecting peritubular capillaries and preventing inflammatory infiltration.

scholarly journals MP240DEVELOPMENT OF AN “IN SITU” RENAL PERFUSION SYSTEM TO STUDY THE ORIGIN OF URINARY BIOMARKERS IN TWO ANIMAL MODELS OF ACUTE KIDNEY INJURY INDUCED BY GENTAMICIN AND ISCHEMIA-REPERFUSION

2017 ◽  
Vol 32 (suppl_3) ◽  
pp. iii514-iii514
Author(s):  
Víctor Blanco-Gozalo ◽  
Laura Prieto-García ◽  
Sandra Sancho-Martínez ◽  
Yaremi Quiros-Luis ◽  
José López-Novoa ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Animal Models ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Perfusion ◽  
Urinary Biomarkers ◽  
Perfusion System

scholarly journals Early antihypertensive treatment and ischemia-induced acute kidney injury

2020 ◽  
Vol 319 (4) ◽  
pp. F563-F570
Author(s):  
Robert Greite ◽  
Katja Derlin ◽  
Bennet Hensen ◽  
Anja Thorenz ◽  
Song Rong ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Acute Kidney Injury ◽  
Antihypertensive Treatment ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Perfusion ◽  
Renal Outcome ◽  
Major Surgery ◽  
Mesangial Matrix ◽  
Matrix Expansion

Acute kidney injury (AKI) frequently complicates major surgery and can be associated with hypertension and progress to chronic kidney disease, but reports on blood pressure normalization in AKI are conflicting. In the present study, we investigated the effects of an angiotensin-converting enzyme inhibitor, enalapril, and a soluble epoxide hydrolase inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), on renal inflammation, fibrosis, and glomerulosclerosis in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. Male CD1 mice underwent unilateral IRI for 35 min. Blood pressure was measured by tail cuff, and mesangial matrix expansion was quantified on methenamine silver-stained sections. Renal perfusion was assessed by functional MRI in vehicle- and TPPU-treated mice. Immunohistochemistry was performed to study the severity of AKI and inflammation. Leukocyte subsets were analyzed by flow cytometry, and proinflammatory cytokines were analyzed by quantitative PCR. Plasma and tissue levels of TPPU and lipid mediators were analyzed by liquid chromatography mass spectrometry. IRI resulted in a blood pressure increase of 20 mmHg in the vehicle-treated group. TPPU and enalapril normalized blood pressure and reduced mesangial matrix expansion. However, inflammation and progressive renal fibrosis were severe in all groups. TPPU further reduced renal perfusion on days 1 and 14. In conclusion, early antihypertensive treatment worsened renal outcome after AKI by further reducing renal perfusion despite reduced glomerulosclerosis.

Diminished NO generation by injured endothelium and loss of macula densa nNOS may contribute to sustained acute kidney injury after ischemia-reperfusion

2009 ◽  
Vol 296 (1) ◽  
pp. F25-F33 ◽  
Author(s):  
Osun Kwon ◽  
Seok-Min Hong ◽  
Ganesan Ramesh
Keyword(s):  
Acute Kidney Injury ◽  
Glomerular Filtration ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Endothelial Damage ◽  
Macula Densa ◽  
Renal Vasculature ◽  
Peritubular Capillaries ◽  
Recovery Group ◽  
Neuronal Nos

In postischemic acute kidney injury (AKI) or acute renal failure, a dissipation of glomerular filtration pressure is associated with an altered renal vascular tone and reactivity, as well as a loss of vascular autoregulation. To test the hypothesis that renal nitric oxide (NO) generation reflects endothelial damage in the kidney after ischemia-reperfusion, we quantified the urinary NO levels and identified the site of its generation in postischemic AKI. Subjects were 50 recipients of cadaveric renal allografts: 15 with sustained AKI and 35 with recovering renal function. Urine and blood samples were obtained after transplant, and intraoperative allograft biopsies were performed to examine NO synthases (NOSs) in the kidney. In the sustained AKI group, urinary nitrite and nitrate excretion (in μmol/g urine creatinine) was lower (12.3 ± 1.8 and 10.0 ± 1.4 on postoperative days 0 and 3) than in the recovery group [20.0 ± 3.6 and 35.1 ± 5.3 ( P < 0.005 vs. sustained AKI on days 0 and 3) on postoperative days 0 and 3]. Endothelial NOS expression diminished from the peritubular capillaries of 6 of 7 subjects in the sustained AKI group but from only 6 of 16 subjects in the recovery group. No differences were observed in the inducible NOS staining pattern between the two groups. Neuronal NOS staining was rarely observed in the macula densae of subjects but was prominent in control tissues. These findings suggest that a diminished NO generation by injured endothelium and loss of macula densa neuronal NOS could impair the vasodilatory ability of the renal vasculature and contribute to the reduction in the glomerular filtration rate in postischemic AKI.

scholarly journals Early Diabetes Aggravates Renal Ischemia/reperfusion-induced Acute Kidney Injury 

2021 ◽  
Author(s):  
Mariana de Ponte ◽  
Vanessa Cardoso ◽  
Juliana Costa-Pessoa ◽  
Maria Oliveira-Souza
Keyword(s):  
Acute Kidney Injury ◽  
Risk Factor ◽  
Mrna Expression ◽  
Ischemia Reperfusion ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Plasma Creatinine ◽  
Ki 67 ◽  
Early Diabetes ◽  
The Impact

Abstract Acute kidney injury (AKI) due to ischemia and reperfusion (IR) can be associated with the progression of chronic kidney injury. In addition, studies suggest that chronic diabetes is an independent risk factor for AKI; however, the impact of early diabetes on the severity of AKI remains unknown. We investigated the effects of early diabetes on the pathophysiology of renal IR-induced AKI. C57BL/6J mice were randomly assigned into the following groups: 1) sham-operated; 2) renal IR; 3) streptozotocin (STZ - 55 mg/kg/day) and sham-operated; and 4) STZ and renal IR. On the 12th day after treatments, the animals were subjected to bilateral IR for 30 minutes followed by reperfusion for 48 hours, and the mice were euthanized by exsanguination. Renal function was assessed by analyzing the plasma creatinine and urea concentrations with biochemical methods. Proteinuria was evaluated using a commercial kit. Kidney tissue was used to evaluate the morphology, gene expression by qPCR, and protein expression by Western blotting. Compared to the sham operated, renal IR resulted in increased plasma creatinine and urea levels, decreased nephrin mRNA expression, increased tubular cast formation, and Kim-1, Ki-67, pro-inflammatory and pro-fibrotic factor mRNA expression. Compared with the sham treatment, STZ treatment resulted in hyperglycemia, but did not induce changes in kidney function or pro-inflammatory or pro-fibrotic factors. However, STZ treatment aggravated renal IR-induced AKI by exacerbating glomerular and tubular injury, inflammation, and the profibrotic response. Early diabetes constitutes a relevant risk factor for renal IR-induced AKI.

scholarly journals Relevant Role of Von Willebrand Factor in Ischemia-Reperfusion Model of Acute Kidney Injury in Mice

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2243-2243
Author(s):  
Shiro Ono ◽  
Hideto Matsui ◽  
Masashi Noda ◽  
Shogo Kasuda ◽  
Yasunori Matsunari ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Blood Flow ◽  
Renal Blood Flow ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Relevant Role ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Acute kidney injury (AKI), an abrupt loss of renal function, is often seen in clinical settings and its mortality remains high even in the developed countries. An adhesive protein von Willebrand factor (VWF) plays a pivotal role in platelet thrombus formation and is recently understood as a key protein in a cross-talk between inflammation and thrombosis. Recent mouse model studies demonstrated that VWF-mediated thrombotic and inflammatory responses could play a role in the disease progression of myocardial infarction or brain stroke. Thus, we assumed that VWF may also be involved in the pathophysiology of AKI, the major cause of which could be an insufficient renal circulation and/or inflammatory cell infiltration in the kidney. To test this hypothesis, we studied the relevant role of VWF in AKI in mouse model of acute ischemia-reperfusion (I/R) kidney injury. All mice used were male, 8-12 weeks of age, healthy and whose right kidney was surgically removed by the standard mouse nephrectomy procedure 1 week prior to the kidney I/R experiment. The preliminary experiments confirmed that surgical removal of mouse right kidney did not affect their general conditions including renal functions. Mice were anesthetized with inhaled isoflurane and then placed in an abdominal position on a heating pad. Surgical incision was given on the left side of back and the left kidney was brought out and kept outside during the operation. Both renal artery and vein were clamped at the renal hilus by a clamping clip for 30 min ischemia. Then a clip was taken off to provoke the reperfusion of renal blood flow, which was monitored by Laser Doppler flowmetry (ALF21, Advance Co, Tokyo, Japan). The kidney was then put back in a body and skin incision was closed. The renal blood flow was measured again 30 h after reperfusion and mice were then sacrificed for blood collection. We compared 15 wild-type (WT) and 16 VWF-gene deleted (knock-out; KO) mice (from The Jackson Laboratory, Bar Harbor, ME). Excess blood loss was not observed in all mice (WT or KO) during whole surgical process. Although no difference was seen immediately after reperfusion, significantly (p < 0.05) higher renal blood flow at 30 h after reperfusion was confirmed in VWF-KO mice, as compared to WT (KO; 24.0±2.3 vs. WT; 15.1±1.46 ml/min/100g of kidney weight, and the reperfusion/base flow ratio: KO; 1.0±0.07 vs. WT; 0.6 ±0.07). Consistent with the renal blood flow data, the serum creatinine value at 30 h after reperfusion were significantly (p < 0.05) lower in VWF-KO mice than WT (KO; 2.77±0.11 vs. WT; 3.15±0.11 mg/dl). Our results suggest that VWF does play a role in the pathogenesis of AKI, in which VWF-dependent thrombotic or inflammatory responses may trigger thrombotic ischemia or endothelial damages of vascular bed in the kidney. Thus, proper functional regulation of VWF would be beneficial for better microcirculation and vessel functions in the kidney, suggesting a novel therapeutic potential against AKI. Disclosures No relevant conflicts of interest to declare.

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