Early antihypertensive treatment and ischemia-induced acute kidney injury

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.

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

Biology of Sex Differences ◽

10.1186/s13293-020-00331-6 ◽

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.

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

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0558 ◽

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.

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Diffusion Weighted Imaging and T2 Mapping Detect Inflammatory Response in the Renal Tissue during Ischemia Induced Acute Kidney Injury in Different Mouse Strains and Predict Renal Outcome

Biomedicines ◽

10.3390/biomedicines9081071 ◽

2021 ◽

Vol 9 (8) ◽

pp. 1071

Author(s):

Robert Greite ◽

Katja Derlin ◽

Dagmar Hartung ◽

Rongjun Chen ◽

Martin Meier ◽

...

Keyword(s):

Acute Kidney Injury ◽

Diffusion Weighted Imaging ◽

T2 Mapping ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Renal Outcome ◽

Mouse Strains ◽

Kidney Volume ◽

Contralateral Kidney ◽

Diffusion Weighted

To characterize ischemia reperfusion injury (IRI)-induced acute kidney injury (AKI) in C57BL/6 (B6) and CD1-mice by longitudinal functional MRI-measurement of edema formation (T2-mapping) and inflammation (diffusion weighted imaging (DWI)). IRI was induced with unilateral right renal pedicle clamping for 35min. 7T-MRI was performed 1 and 14 days after surgery. DWI (7 b-values) and multiecho TSE sequences (7 TE) were acquired. Parameters were quantified in relation to the contralateral kidney on day 1 (d1). Renal MCP-1 and IL-6-levels were measured by qPCR and serum-CXCL13 by ELISA. Immunohistochemistry for fibronectin and collagen-4 was performed. T2-increase on d1 was higher in the renal cortex (127 ± 5% vs. 94 ± 6%, p < 0.01) and the outer stripe of the outer medulla (141 ± 9% vs. 111 ± 9%, p < 0.05) in CD1, indicating tissue edema. Medullary diffusivity was more restricted in CD1 than B6 (d1: 73 ± 3% vs. 90 ± 2%, p < 0.01 and d14: 77 ± 5% vs. 98 ± 3%, p < 0.01). Renal MCP-1 and IL-6-expression as well as systemic CXCL13-release were pronounced in CD1 on d1 after IRI. Renal fibrosis was detected in CD1 on d14. T2-increase and ADC-reduction on d1 correlated with kidney volume loss on d14 (r = 0.7, p < 0.05; r = 0.6, p < 0.05) and could serve as predictive markers. T2-mapping and DWI evidenced higher susceptibility to ischemic AKI in CD1 compared to B6.

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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

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfx166.mp240 ◽

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

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Targeting acute kidney injury in COVID-19

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa231 ◽

2020 ◽

Vol 35 (10) ◽

pp. 1652-1662 ◽

Cited By ~ 3

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.

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Female and male mice have differential longterm cardiorenal outcomes following a matched degree of ischemia–reperfusion acute kidney injury

Scientific Reports ◽

10.1038/s41598-021-04701-x ◽

2022 ◽

Vol 12 (1) ◽

Author(s):

Danielle E. Soranno ◽

Peter Baker ◽

Lara Kirkbride-Romeo ◽

Sara A. Wennersten ◽

Kathy Ding ◽

...

Keyword(s):

Blood Pressure ◽

Acute Kidney Injury ◽

Mitochondrial Function ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Cardiovascular Outcomes ◽

Male Mice ◽

Male And Female ◽

Female Mice

AbstractAcute kidney injury (AKI) is common in patients, causes systemic sequelae, and predisposes patients to long-term cardiovascular disease. To date, studies of the effects of AKI on cardiovascular outcomes have only been performed in male mice. We recently demonstrated that male mice developed diastolic dysfunction, hypertension and reduced cardiac ATP levels versus sham 1 year after AKI. The effects of female sex on long-term cardiac outcomes after AKI are unknown. Therefore, we examined the 1-year cardiorenal outcomes following a single episode of bilateral renal ischemia–reperfusion injury in female C57BL/6 mice using a model with similar severity of AKI and performed concomitantly to recently published male cohorts. To match the severity of AKI between male and female mice, females received 34 min of ischemia time compared to 25 min in males. Serial renal function, echocardiograms and blood pressure assessments were performed throughout the 1-year study. Renal histology, and cardiac and plasma metabolomics and mitochondrial function in the heart and kidney were evaluated at 1 year. Measured glomerular filtration rates (GFR) were similar between male and female mice throughout the 1-year study period. One year after AKI, female mice had preserved diastolic function, normal blood pressure, and preserved levels of cardiac ATP. Compared to males, females demonstrated pathway enrichment in arginine metabolism and amino acid related energy production in both the heart and plasma, and glutathione in the plasma. Cardiac mitochondrial respiration in Complex I of the electron transport chain demonstrated improved mitochondrial function in females compared to males, regardless of AKI or sham. This is the first study to examine the long-term cardiac effects of AKI on female mice and indicate that there are important sex-related cardiorenal differences. The role of female sex in cardiovascular outcomes after AKI merits further investigation.

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Renal PKC-ε deficiency attenuates acute kidney injury and ischemic allograft injury via TNF-α-dependent inhibition of apoptosis and inflammation

AJP Renal Physiology ◽

10.1152/ajprenal.00372.2013 ◽

2014 ◽

Vol 307 (6) ◽

pp. F718-F726 ◽

Cited By ~ 22

Author(s):

Song Rong ◽

Katja Hueper ◽

Torsten Kirsch ◽

Robert Greite ◽

Christian Klemann ◽

...

Keyword(s):

Acute Kidney Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Neutrophil Infiltration ◽

Major Surgery ◽

Severe Renal Failure ◽

Tnf Α ◽

Apoptosis And Inflammation ◽

Deficient Mice

Acute kidney injury (AKI) increases the risk of morbidity and mortality after major surgery and transplantation. We investigated the effect of PKC-ε deficiency on AKI and ischemic allograft damage after kidney transplantation. PKC-ε-deficient and wild type (WT) control mice were subjected to 35 min of renal pedicle clamping to induce AKI. PKC-ε deficiency was associated with a marked improvement in survival and an attenuated loss of kidney function. Furthermore, functional MRI experiments revealed better renal perfusion in PKC-ε-deficient mice than in WT mice one day after IRI. Acute tubular necrosis and neutrophil infiltration were markedly reduced in PKC-ε-deficient mice. To determine whether this resistance to ischemia-reperfusion injury resulted from changes in local renal cells or infiltrating leukocytes, we studied a life-supporting renal transplant model of ischemic graft injury. We transplanted kidneys from H2b PKC-ε-deficient mice (129/SV) and their corresponding WT littermates into major histocompatibility complex-incompatible H2d recipients (BALB/c) and induced ischemic graft injury by prolonged cold ischemia time. Recipients of WT allografts developed severe renal failure and died within 10 days of transplantation. Recipients of PKC-ε-deficient allografts had better renal function and survival; they had less generation of ROS and upregulation of proinflammatory proteins (i.e., ICAM-1, inducible nitric oxide synthase, and TNF-α) and showed less tubular epithelial cell apoptosis and inflammation in their allografts. These data suggest that local renal PKC-ε expression mediates proapoptotic and proinflammatory signaling and that an inhibitor of PKC-ε signaling could be used to prevent hypoxia-induced AKI.

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Impaired Tubular Reabsorption Is the Main Mechanism Explaining Increases in Urinary NGAL Excretion Following Acute Kidney Injury in Rats

Toxicological Sciences ◽

10.1093/toxsci/kfaa029 ◽

2020 ◽

Vol 175 (1) ◽

pp. 75-86 ◽

Cited By ~ 1

Author(s):

Sandra M Sancho-Martínez ◽

Víctor Blanco-Gozalo ◽

Yaremi Quiros ◽

Laura Prieto-García ◽

María J Montero-Gómez ◽

...

Keyword(s):

Acute Kidney Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Renal Perfusion ◽

Tubular Reabsorption ◽

Urinary Ngal ◽

Neutrophil Gelatinase Associated Lipocalin ◽

Perfusion Studies ◽

Glomerular Filtrate

Abstract Neutrophil gelatinase-associated lipocalin (NGAL) is a secreted low-molecular weight iron-siderophore-binding protein. NGAL overexpression in injured tubular epithelia partly explains its utility as a sensitive and early urinary biomarker of acute kidney injury (AKI). Herein, we extend mechanistic insights into the source and kinetics of urinary NGAL excretion in experimental AKI. Three models of experimental AKI were undertaken in adult male Wistar rats; renal ischemia-reperfusion injury (IRI) and gentamicin (G) and cisplatin (Cisp) nephrotoxicity. Alongside standard histological and biochemical assessment of AKI, urinary NGAL excretion rate, plasma NGAL concentration, and renal NGAL mRNA/protein expression were assessed. In situ renal perfusion studies were undertaken to discriminate direct shedding of NGAL to the urine from addition of NGAL to the urine secondary to alterations in the tubular handling of glomerular filtrate-derived protein. Renal NGAL expression and urinary excretion increased in experimental AKI. In acute studies in both the IRI and G models, direct renal perfusion with Kreb’s buffer eliminated urinary NGAL excretion. Addition of exogenous NGAL to the Kreb’s buffer circuit, reestablishment of perfusion with systemic blood or reperfusion with renal vein effluent restored high levels of urinary NGAL excretion. Urinary NGAL excretion in AKI arises in large proportion from reduced reabsorption from the glomerular filtrate. Hence, subclinical cellular dysfunction could increase urinary NGAL, particularly in concert with elevations in circulating prerenal NGAL and/or pharmacological inhibition of tubular reabsorption. More granular interpretation of urinary NGAL measurements could optimize the scope of its clinical utility as a biomarker of AKI.

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Extended Sessions of Polymyxin-B Immobilized Fiber Column Hemoperfusion Ameliorate Renal Outcome and Mortality in Septic Shock with Acute Kidney Injury

Blood Purification ◽

10.1159/000488639 ◽

2018 ◽

Vol 46 (2) ◽

pp. 81-89 ◽

Cited By ~ 1

Author(s):

Hiroshi Maekawa ◽

Kousuke Negishi

Keyword(s):

Blood Pressure ◽

Septic Shock ◽

Acute Kidney Injury ◽

Renal Replacement Therapy ◽

Clinical Outcomes ◽

Kidney Injury ◽

Polymyxin B ◽

Renal Outcome ◽

Control Methods ◽

The Mean

Background/Aims: Polymyxin-B (PMX) treatment has been reported to decrease mortality in patients with septic shock and acute kidney injury (AKI). In this study, we aimed to evaluate whether extended sessions of PMX (Ext-PMX) immobilized fiber column hemoperfusion ameliorate clinical outcomes in patients complicated with septic shock and AKI without surgical control. Methods: Twenty-two patients with nonsurgical septic shock and AKI who received PMX were included. They were divided according to the duration of PMX treatment: Ext-PMX and standard PMX (Std-PMX). Results: The mean blood pressure increased and inotrope requirement decreased within 24 h after PMX initiation. The median value of predicted mortality was 52.5%, and the 28-day mortalities in the Ext-PMX and Std-PMX groups were 44.4 and 75% respectively. Renal replacement therapy (RRT) was also initiated in 17 patients, and renal insufficiency was recovered. Conclusion: Ext-PMX combined with RRT improved clinical outcomes in patients with nonsurgical septic shock and AKI.

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Renoprotective Effects of DNAse-I Treatment in a Rat Model of Ischemia/Reperfusion-Induced Acute Kidney Injury

American Journal of Nephrology ◽

10.1159/000445546 ◽

2016 ◽

Vol 43 (3) ◽

pp. 195-205 ◽

Cited By ~ 16

Author(s):

Victoria Peer ◽

Ramzia Abu Hamad ◽

Sylvia Berman ◽

Shai Efrati

Keyword(s):

Acute Kidney Injury ◽

Inflammatory Diseases ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Treated Group ◽

Renal Perfusion ◽

Dnase I ◽

Sprague Dawley ◽

Contralateral Kidney ◽

Debris Accumulation

Background: Massive DNA destruction/accumulation of cell-free DNA debris is a sensitive biomarker of progressive organ/tissue damage. Deleterious consequences of DNA debris accumulation are evident in cardiac ischemia, thrombosis, auto-inflammatory diseases, SLE-induced lupus nephritis and cystic fibrosis. In case of renal pathologies, degradation and elimination of DNA debris are suppressed, due to downregulated DNAse-I activity within the diseased kidneys. The aim of the current study was to evaluate whether exogenous DNAse-I administration might exert renoprotective effects in the setting of acute kidney injury (AKI or acute renal failure). Methods: Sprague-Dawley rats underwent unilateral nephrectomy, with simultaneous clamping of contralateral kidney artery. The treated group received DNAse-I injection before discontinuing anesthesia. Positive (ischemic) controls received saline injection. Negative (non-ischemic) controls were either non-operated or subjected to surgery of similar duress and duration without ischemia. Renal perfusion was evaluated using the Laser-Doppler technique. Blood was procured for evaluating DNAse-I activity, renal functioning, renal perfusion. The kidneys were allocated for histopathologic examinations and for the evaluation of renal hypoxia, intra-renal apoptosis and proliferation. Results: Contrary to the situation in untreated ischemic rats, renal perfusion was significantly improved in DNAse-treated animals, concomitantly with significant amelioration of damage to renal functioning and tissue integrity. Treatment with DNAse-I significantly decreased the ischemia-induced renal hypoxia and apoptosis, simultaneously stimulating renal cell proliferation. Exogenous DNAse-I administration accelerated the clearance of intra-renal apoptotic DNA debris. Conclusion: Functional/histologic hallmarks of renal injury were ameliorated, renal functioning improved, intra-renal hypoxia decreased and intra-renal regeneration processes were activated. Thus, DNAse-I treatment protected the kidney from deleterious consequences of ischemia-induced AKI.

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