scholarly journals Population Pharmacokinetic Model-Based Evaluation of Intact Oxaliplatin in Rats with Acute Kidney Injury

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6382
Author(s):  
Shinji Kobuchi ◽  
Miyu Kai ◽  
Yukako Ito
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
Dose Reduction ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Model Based ◽  
Population Pk ◽  
The Impact

Acute kidney injury (AKI) complicates the dosing strategies of oxaliplatin (L-OHP) and the requirement for L-OHP dose reduction in patients with renal failure remains controversial. The objective of this study is to assess the impact of AKI on the pharmacokinetics (PK) of intact L-OHP and simulate the relationship between the degree of renal function and intact L-OHP exposures using a population PK model. Intact L-OHP concentrations in plasma and urine after L-OHP administration were measured in mild and severe AKI models established in rats through renal ischemia-reperfusion. Population PK modeling and simulation were performed. There were no differences among rats in the area under the plasma concentration–time curve of intact L-OHP after intravenous L-OHP administrations. Nevertheless, the amount of L-OHP excretion after administration of 8 mg/kg L-OHP in mild and severe renal dysfunction rats was 63.5% and 37.7%, respectively, and strong correlations were observed between biochemical renal function markers and clearance of intact L-OHP. The population PK model simulated well the observed levels of intact L-OHP in AKI model rats. The population PK model-based simulation suggests that dose reduction is unnecessary for patients with mild to moderate AKI.

scholarly journals Comment on “Nuclear receptor PXR targets AKR1B7 to protect mitochondrial metabolism and renal function in AKI”

2021 ◽  
Vol 13 (593) ◽  
pp. eabd0214
Author(s):  
Zhilin Luan ◽  
Wenhua Ming ◽  
Cong Zhang ◽  
Xiaoxiao Huo ◽  
Feng Zheng ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
Nuclear Receptor ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Pregnane X Receptor ◽  
Mitochondrial Metabolism

The nuclear pregnane X receptor may not protect against ischemia/reperfusion-induced acute kidney injury in mice.

scholarly journals Hydroxyethyl Starch 130/0.42 Effect’s on Renal Function in Patients After Cardiac Surgery: A Retrospective Cohort Analysis

2020 ◽  
Author(s):  
Benedict Morath ◽  
Andreas Meid ◽  
Johannes Rickmann ◽  
Jasmin Soethoff ◽  
Markus Verch ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
Cardiac Surgery ◽  
Kidney Function ◽  
Hydroxyethyl Starch ◽  
Retrospective Cohort ◽  
Cohort Analysis ◽  
Kidney Injury ◽  
Retrospective Cohort Analysis ◽  
The Impact

Abstract Background: Fluid management is an everyday challenge in intensive care units worldwide. Data from recent trials suggest that the use of hydroxyethyl starch leads to a higher rate of acute kidney injury and mortality in septic patients. Evidence on the safety of hydroxyethyl starch used in postoperative cardiac surgery patients is lacking Methods: The aim was to determine the impact of postoperatively administered hydroxyethylstarch 130/0.42 on renal function and 90-day mortality compared to with or without balanced crystalloids in patients after elective cardiac surgery. A retrospective cohort analysis was performed including 2245 patients undergoing elective coronary artery bypass grafting or, aortic valve replacement, or a combination of both between 2015 - 2019. Acute kidney injury was defined according to the ‘kidney disease improving global outcomes’ criteria. Multivariate logistic regression yielded adjusted associations of postoperative hydroxyethyl starch administration with acute kidney injury during hospital stay and 90-day mortality. Linear mixed-effects models predicted trajectories of estimated glomerular filtration rates over the postoperative period to explore the impact of dosage and timing of hydroxyethyl starch administration.Results: A total of 1009 patients (45.0 %) suffered from acute kidney injury. Significantly less acute kidney injury of any stage occurred in patients receiving hydroxyethyl starch compared to patients receiving only crystalloids for fluid resuscitation (43.7 % vs. 51.2 % p=0.008). In multivariate analysis, the administration of hydroxyethyl starch showed a protective effect (OR 0.89 95% confidence interval (CI) (0.82-0.96)) which was less prominent in patients receiving only crystalloids (OR 0.98, 95% CI (0.95-1.00)). No association between hydroxyethyl starch and 90-day mortality (OR 1.05 95% CI (0.88-1.25)) was detected. Renal function trajectories were dose-dependent and biphasic and hydroxyethyl starch could even slow down the late postoperative decline of kidney function.Conclusion: This study showed no association between hydroxyethyl starch and the postoperative occurrence of acute kidney injury and may add evidence to the discussion about the use of hydroxyethyl starch in cardiac surgery patients. In addition, hydroxyethyl starch administered early after surgery in adequate low doses might even prevent the decline of the kidney function after cardiac surgery.

The impact of minimal invasive extracorporeal circulation on postoperative kidney function

Perfusion ◽  
2020 ◽  
pp. 026765912095460
Author(s):  
Ara Shwan Media ◽  
Peter Juhl-Olsen ◽  
Nils Erik Magnusson ◽  
Ivy Susanne Modrau
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
Kidney Function ◽  
Extracorporeal Circulation ◽  
Artery Bypass ◽  
Bypass Graft ◽  
Kidney Injury ◽  
Minimal Invasive ◽  
Mortality And Morbidity ◽  
The Impact

Introduction: Acute kidney injury following cardiac surgery is a frequent complication associated with increased mortality and morbidity. Minimal invasive extracorporeal circulation is suggested to preserve postoperative renal function. The aim of this study was to assess the impact of minimal invasive versus conventional extracorporeal circulation on early postoperative kidney function. Methods: Randomized controlled trail including 60 patients undergoing elective stand-alone coronary artery bypass graft surgery and allocated in a 1:1 ratio to either minimal invasive (n = 30) or conventional extracorporeal circulation (n = 30). Postoperative kidney injury was assessed by elevation of plasma neutrophil gelatinase-associated lipocalin (NGAL), a sensitive tubular injury biomarker. In addition, we assessed changes in estimated glomerular filtration rate (eGFR), and the incidence of acute kidney injury according to the Acute Kidney Injury Network (AKIN) classification. Results: We observed no differences between groups regarding increase of plasma NGAL (p = 0.31) or decline of eGFR (p = 0.82). In both groups, 6/30 patients developed acute kidney injury according to the AKIN classification, all regaining preoperative renal function within 30 days. Conclusion: Our findings challenge the superiority of minimal invasive compared to conventional extracorporeal circulation in terms of preservation of renal function following low-risk coronary surgery.

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 Recurrent acute kidney injury: predictors and impact in a large population-based cohort

2019 ◽  
Vol 35 (8) ◽  
pp. 1361-1369 ◽  
Author(s):  
Jennifer Holmes ◽  
John Geen ◽  
John D Williams ◽  
Aled O Phillips
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
Patient Outcomes ◽  
Large Population ◽  
Kidney Injury ◽  
Population Based ◽  
First Episode ◽  
Single Episode ◽  
Subsequent Episode ◽  
The Impact

Abstract Background This study examined the impact of recurrent episodes of acute kidney injury (AKI) on patient outcomes. Methods The Welsh National electronic AKI reporting system was used to identify all cases of AKI in patients ≥18 years of age between April 2015 and September 2018. Patients were grouped according to the number of AKI episodes they experienced with each patient’s first episode described as their index episode. We compared the demography and patient outcomes of those patients with a single AKI episode with those patients with multiple AKI episodes. Analysis included 153 776 AKI episodes in 111 528 patients. Results Of those who experienced AKI and survived their index episode, 29.3% experienced a second episode, 9.9% a third episode and 4.0% experienced fourth or more episodes. Thirty-day mortality for those patients with multiple episodes of AKI was significantly higher than for those patients with a single episode (31.3% versus 24.9%, P &lt; 0.001). Following a single episode, recovery to baseline renal function at 30 days was achieved in 83.6% of patients and was significantly higher than for patients who had repeated episodes (77.8%, P &lt; 0.001). For surviving patients, non-recovery of renal function following any AKI episode was significantly associated with a higher probability of a further AKI episode (33.4% versus 41.0%, P &lt; 0.001). Furthermore, with each episode of AKI the likelihood of a subsequent episode also increased (31.0% versus 43.2% versus 51.2% versus 51.7% following a first, second, third and fourth episode, P &lt; 0.001 for all comparisons). Conclusions The results of this study provide an important contribution to the debate regarding the need for risk stratification for recurrent AKI. The data suggest that such a tool would be useful given the poor patient and renal outcomes associated with recurrent AKI episodes as highlighted by this study.

scholarly journals Human amniotic epithelial cells ameliorate kidney damage in ischemia-reperfusion mouse model of acute kidney injury

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Yifei Ren ◽  
Ying Chen ◽  
Xizi Zheng ◽  
Hui Wang ◽  
Xin Kang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Kidney Injury ◽  
Renal Function ◽  
Mouse Model ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Mouse Bone Marrow ◽  
Tissue Integration

Abstract Background Acute kidney injury (AKI) is a common clinical disease with complex pathophysiology and limited therapeutic choices. This prompts the need for novel therapy targeting multiple aspects of this disease. Human amnion epithelial cell (hAEC) is an ideal stem cell source. Increasing evidence suggests that exosomes may act as critical cell–cell communicators. Accordingly, we assessed the therapeutic potential of hAECs and their derived exosomes (hAECs-EXO) in ischemia reperfusion mouse model of AKI and explored the underlying mechanisms. Methods The hAECs were primary cultured, and hAECs-EXO were isolated and characterized. An ischemic-reperfusion injury-induced AKI (IRI-AKI) mouse model was established to mimic clinical ischemic kidney injury with different disease severity. Mouse blood creatinine level was used to assess renal function, and kidney specimens were processed to detect cell proliferation, apoptosis, and capillary density. Macrophage infiltration was analyzed by flow cytometry. hAEC-derived exosomes (hAECs-EXO) were used to treat hypoxia-reoxygenation (H/R) injured HK-2 cells and mouse bone marrow-derived macrophages to evaluate their protective effect in vitro. Furthermore, hAECs-EXO were subjected to liquid chromatography-tandem mass spectrometry for proteomic profiling. Results We found that systematically administered hAECs could improve mortality and renal function in IRI-AKI mice, decrease the number of apoptotic cells, prevent peritubular capillary loss, and modulate kidney local immune response. However, hAECs showed very low kidney tissue integration. Exosomes isolated from hAECs recapitulated the renal protective effects of their source cells. In vitro, hAECs-EXO protected HK-2 cells from H/R injury-induced apoptosis and promoted bone marrow-derived macrophage polarization toward M2 phenotype. Proteomic analysis on hAECs-EXO revealed proteins involved in extracellular matrix organization, growth factor signaling pathways, cytokine production, and immunomodulation. These findings demonstrated that paracrine of exosomes might be the key mechanism of hAECs in alleviating renal ischemia reperfusion injury. Conclusions We reported hAECs could improve survival and ameliorate renal injury in mice with IRI-AKI. The anti-apoptotic, pro-angiogenetic, and immunomodulatory capabilities of hAECs are at least partially, through paracrine pathways. hAECs-EXO might be a promising clinical therapeutic tool, overcoming the weaknesses and risks associated with the use of native stem cells, for patients with AKI.

scholarly journals Human amniotic epithelial cells improve kidney repair in ischemia-reperfusion mouse model of acute kidney injury

2020 ◽  
Author(s):  
Yifei Ren ◽  
Ying Chen ◽  
Xizi Zheng ◽  
Hui Wang ◽  
Xin Kang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Kidney Injury ◽  
Renal Function ◽  
Epithelial Cells ◽  
Mouse Model ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Mouse Bone Marrow ◽  
Tissue Integration

Abstract Background: Acute kidney injury (AKI) is a common clinical disease with complex pathophysiology and very limited therapeutic choices. This prompts the need for novel therapy targeting multiple aspects of this disease. Human amnion epithelial cells (hAECs) are ideal alternative stem cell source for regenerative medicine. Increasing evidence suggests that hAEC-derived exosomes (hAECs-EXO) may act as novel cell–cell communicators. Accordingly, we assessed the therapeutic potential of hAECs in ischemia reperfusion mouse model of AKI and explored the underlying mechanisms.Methods: The hAECs were primary cultured and hAECs-EXO were isolated and characterized. An ischemic renal injury mouse model was established to mimic different severity of the kidney injury. Mouse blood creatinine level was used to assess renal function and kidney specimens were processed to detect cell proliferation, apoptosis and angiogenesis. Immune cells infiltration was analyzed by flow cytometry. hAECs-EXO was used to treat hypoxia-reoxygenation (H/R) injured HK2 cells and mouse bone marrow-derived macrophages to evaluate their protective effect in vitro. Furthermore, hAEC exosomes were subjected to liquid chromatography-tandem mass spectrometry for proteomic profiling. Results: We found that systematically administered hAECs could improve mortality and renal function in IRI mice; decrease the number of apoptotic cells; promote peritubular capillary regeneration and modulate kidney local immune response. However, hAECs showed very low kidney tissue integration. Exosomes isolated from hAECs recapitulated the renal protective effects of their parent cells. In vitro, hAECs-EXO protected HK-2 cells from H/R injury-induced apoptosis and promoted bone marrow-derived macrophage polarization toward M2 phenotype. Proteomic analysis on hAECs-EXO revealed proteins involved in extracellular matrix organization, growth factor signaling pathways, cytokine production and immunomodulation. These findings demonstrated that paracrine of exosomes might be a key mechanism by hAECs mediating kidney functional recovery in AKI.Conclusions: We first reported hAECs could improve mortality and renal repair in mice with ischemia-reperfusion injury. The anti-apoptotic, pro-angiogenetic, and immunomodulatory capabilities of hAECs at least partially, through paracrine pathways. The renoprotective effects of hAECs-EXO might be a promising clinical therapeutic tool, overcoming the weaknesses and risks associated with the use of native stem cells for patients with AKI.

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 &gt;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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