Cell-Free Hemoglobin in Acute Kidney Injury after Lung Transplantation and Experimental Renal Ischemia/Reperfusion

Greite, Robert; Wang, Li; Gohlke, Lukas; Schott, Sebastian; Kreimann, Kirill; Doricic, Julian; Leffler, Andreas; Tudorache, I.; Salman, J.; Natanov, Ruslan; Ius, F.; Fegbeutel, Christine; Haverich, Axel; Lichtinghagen, Ralf; Chen, Rongjun; Rong, Song; Haller, Hermann; Vijayan, Vijith; Gram, Magnus; Scheffner, Irina; Gueler, Faikah; Gwinner, Wilfried; Immenschuh, Stephan

doi:10.3390/ijms232113272

Cited by 7 publications

(5 citation statements)

References 41 publications

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“…The accumulation of hemoglobin in proximal tubules was reported to deteriorate AKI induced by cisplatin or ischemic-reperfusion [ 22 ]. Patients with postoperative AKI also tend to be detected with higher cell-free hemoglobin than those without AKI [ 23 ]. Our results in subgroup analysis indicate that the association between ALBI grade and in-hospital mortality was more significant in patients with depressed hemoglobin (<12 g/dL).…”

Section: Discussionmentioning

confidence: 99%

ALBI Grade Is Associated with Clinical Outcomes of Critically Ill Patients with AKI: A Cohort Study with Cox Regression and Propensity Score Matching

Yang,

Yu,

Peng

et al. 2024

Mediators of Inflammation

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Background. The albumin–bilirubin (ALBI) grade has surfaced as a viable substitute for assessing liver functional reserve in individuals afflicted with hepatocellular carcinoma (HCC). ALBI grade also demonstrates the capacity to stratify distinct patient subcohorts bearing disparate prognostic implications in not only HCC but also other inflammatory diseases like acute pancreatitis. However, the association between ALBI grade and clinical outcomes of acute kidney injury (AKI) remains mysterious. Methods. The dataset was sourced from the Multiparameter Intelligent Monitoring in Intensive Care Database IV (MIMIC‐IV) version 2.0. ALBI grade was calculated in a nomogram utilizing albumin and bilirubin. In order to ascertain the connection between ALBI grades and clinical outcomes of patients with AKI, Cox proportional hazards regression analysis was employed with in‐hospital, 30‐ and 90‐day mortality as end points, respectively. The Kaplan–Meier (K–M) curve was employed to gauge the cumulative incidence of mortality based on various ALBI grades. To explore potential nonlinear relationships, the Restricted Cubic Spline (RCS) approach was adopted. Furthermore, a subgroup analysis was conducted to validate the durability of the correlation between ALBI grade and in‐hospital mortality. Furthermore, equilibrium of confounding variables was also achieved through the application of propensity score matching (PSM). Results. The study encompassed a total of 12,518 patients (ALBI grade 1 : 2878, grade 2 : 6708, and grade 3 : 2932). Patients with heightened ALBI grades displayed a significant correlation with increased mortality in both univariate and various multivariate Cox regression models. RCS depicted a predominantly linear relationship. The robustness of the correlation was also affirmed across multifarious subpopulations through subgroup analysis. The association still remains after PSM. Conclusion. Elevated ALBI grade was associated with worse clinical outcomes of critically ill patients with AKI.

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Section: Discussionmentioning

confidence: 99%

ALBI Grade Is Associated with Clinical Outcomes of Critically Ill Patients with AKI: A Cohort Study with Cox Regression and Propensity Score Matching

Yang,

Yu,

Peng

et al. 2024

Mediators of Inflammation

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“…Unstained entire kidney sections were obtained as above, deparaffinized, and fluorescently labeled using polyclonal rabbit anti-mouse A1M antibody (developed in-house) [ 28 ] and Alexa 488-coupled goat anti-rabbit secondary antibody (Invitrogen, Waltham, MA) and mounted with Prolong Diamond antifade mountant with DAPI (4',6-diamidino-2-phenylindole; Invitrogen). Images were obtained from one entire kidney section per mouse treated with E. coli O157:H7 (n = 9) or PBS (n = 4).…”

Section: Methodsmentioning

confidence: 99%

Red blood cell-derived arginase release in hemolytic uremic syndrome

Friberg,

Arvidsson,

Tontanahal

et al. 2024

J Transl Med

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Background Hemolysis is a cardinal feature of hemolytic uremic syndrome (HUS) and during hemolysis excess arginase 1 is released from red blood cells. Increased arginase activity leads to reduced L-arginine, as it is converted to urea and L-ornithine, and thereby reduced nitric oxide bioavailability, with secondary vascular injury. The objective of this study was to investigate arginase release in HUS patients and laboratory models and correlate arginase levels to hemolysis and kidney injury. Methods Two separate cohorts of patients (n = 47 in total) with HUS associated with Shiga toxin-producing enterohemorrhagic E. coli (EHEC) and pediatric controls (n = 35) were investigated. Two mouse models were used, in which mice were either challenged intragastrically with E. coli O157:H7 or injected intraperitoneally with Shiga toxin 2. An in vitro model of thrombotic microangiopathy was developed in which Shiga toxin 2- and E. coli O157 lipopolysaccharide-stimulated human blood cells combined with ADAMTS13-deficient plasma were perfused over glomerular endothelial cells. Two group statistical comparisons were performed using the Mann–Whitney test, multiple groups were compared using the Kruskal–Wallis test followed by Dunn’s procedure, the Wilcoxon signed rank test was used for paired data, or linear regression for continuous variables. Results HUS patients had excessively high plasma arginase 1 levels and activity (conversion of L-arginine to urea and L-ornithine) during the acute phase, compared to remission and controls. Arginase 1 levels correlated with lactate dehydrogenase activity, indicating hemolysis, as well as the need for dialysis treatment. Patients also exhibited high levels of plasma alpha-1-microglobulin, a heme scavenger. Both mouse models exhibited significantly elevated plasma arginase 1 levels and activity. Plasma arginase 1 levels correlated with lactate dehydrogenase activity, alpha-1-microglobulin and urea levels, the latter indicative of kidney dysfunction. In the in vitro model of thrombotic microangiopathy, bioactive arginase 1 was released and levels correlated to the degree of hemolysis. Conclusions Elevated red blood cell-derived arginase was demonstrated in HUS patients and in relevant in vivo and in vitro models. The excessively high arginase levels correlated to the degree of hemolysis and kidney dysfunction. Thus, arginase inhibition should be investigated in HUS.

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“…Whereas the liver can convert free haemoglobin into bilirubin and excrete it into bile during multi-day perfusion (11,19), free haemoglobin will accumulate during kidney perfusion. This poses a serious problem given that the kidney is extremely susceptible to supraphysiological levels of cell free haemoglobin, with acute kidney injury (AKI) as a common consequence (20)(21)(22)(23)(24)(25). Cell free haemoglobin was identified as functional second hit that exacerbates ischemia-reperfusion-injury (IRI) to overt AKI in a mouse model (23).…”

Section: Introductionmentioning

confidence: 99%

“…This poses a serious problem given that the kidney is extremely susceptible to supraphysiological levels of cell free haemoglobin, with acute kidney injury (AKI) as a common consequence (20)(21)(22)(23)(24)(25). Cell free haemoglobin was identified as functional second hit that exacerbates ischemia-reperfusion-injury (IRI) to overt AKI in a mouse model (23). Therefore, we postulate that omission of oxygen carriers, and thus an acellular perfusion approach will better support multi-day kidney preservation.…”

Section: Introductionmentioning

confidence: 99%

Advancing multi-day ex vivo kidney perfusion using spatially resolved metabolomics

Haan

Witjas

Graaf

et al. 2023

Preprint

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The ability to preserve metabolically active kidneys ex vivo for multiple days may permit reconditioning, repair and regeneration of deceased donor kidneys. However, the kidneys high metabolic demand limits its functional preservation. Current approaches focus on normothermic machine perfusion (NMP) at 37C or hypothermic machine perfusion (HMP) at 4-8C. At normothermia, kidneys are metabolically active but ex vivo preservation is limited to hours. During hypothermia kidneys can be preserved up to 24 hours but are metabolically inactive and suffer cold-induced injury. Therefore, we revisited sub normothermic perfusion (at 25C) as an alternative approach to preserve human kidneys in a metabolically active state for extended periods of time. In a custom-made platform that includes a cell-free perfusate enriched with TCA cycle fuels, urine recirculation, and continuous hemofiltration we perfused discarded human kidneys up to 8 days. Using spatially resolved single cell resolution isotope tracing we demonstrate active metabolism in all the different renal cell types over this period. However, beyond 4 days cell composition of nephron segments assessed with spatial lipidomics changed substantially and injury markers such as NGAL and LDH increased in the perfusate. Up to 4 days, perfused human discarded donor kidneys maintained metabolic fluxes, functional parameters and allow for reperfusion using a porcine auto transplantation model. These data underpin that extended multi-day metabolic preservation of human kidneys is achievable using a sub normothermic perfusion platform.

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Cell-Free Hemoglobin in Acute Kidney Injury after Lung Transplantation and Experimental Renal Ischemia/Reperfusion

Cited by 7 publications

References 41 publications

ALBI Grade Is Associated with Clinical Outcomes of Critically Ill Patients with AKI: A Cohort Study with Cox Regression and Propensity Score Matching

ALBI Grade Is Associated with Clinical Outcomes of Critically Ill Patients with AKI: A Cohort Study with Cox Regression and Propensity Score Matching

Red blood cell-derived arginase release in hemolytic uremic syndrome

Advancing multi-day ex vivo kidney perfusion using spatially resolved metabolomics

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