Muscle injury (rhabdomyolysis) and subsequent deposition of myoglobin in the kidney causes renal vasoconstriction and renal failure. We tested the hypothesis that myoglobin induces oxidant injury to the kidney and the formation of F 2 -isoprostanes, potent renal vasoconstrictors formed during lipid peroxidation. In low density lipoprotein (LDL), myoglobin induced a 30-fold increase in the formation of F 2 -isoprostanes by a mechanism involving redox cycling between ferric and ferryl forms of myoglobin. In an animal model of rhabdomyolysis, urinary excretion of F 2 -isoprostanes increased by 7.3-fold compared with controls. Administration of alkali, a treatment for rhabdomyolysis, improved renal function and significantly reduced the urinary excretion of F 2 -isoprostanes by ϳ80%. EPR and UV spectroscopy demonstrated that myoglobin was deposited in the kidneys as the redox competent ferric myoglobin and that it's concentration was not decreased by alkalinization. Kinetic studies demonstrated that the reactivity of ferryl myoglobin, which is responsible for inducing lipid peroxidation, is markedly attenuated at alkaline pH. This was further supported by demonstrating that myoglobin-induced oxidation of LDL was inhibited at alkaline pH. These data strongly support a causative role for oxidative injury in the renal failure of rhabdomyolysis and suggest that the protective effect of alkalinization may be attributed to inhibition of myoglobin-induced lipid peroxidation.
Bilirubin (Bil) interferes with creatinine (Cr) measurement. Different laboratory methods are used to overcome this problem. Model for end-stage liver disease (MELD) scoring incorporates Cr and is used to prioritize patients for liver transplantation. Thus, MELD scores may vary with different Cr measurements influencing patients' priority. Our aim was to evaluate 4 different Cr assays (O'Leary modified Jaffe [mJCr], compensated [rate blanked] kinetic Jaffe [cJCr], enzymatic [ECr], and standard kinetic Jaffe [JCr]) in patients with abnormal liver function tests and assess changes in MELD score. A total of 403 consecutive samples from 158 patients' Cr assays were evaluated.. Bland-Altman plots and MELD scores were also evaluated for each assay. Agreement was found to be poor among all Cr assays. Increased variability in Cr occurred with increasing Bil concentrations: Bil Ͻ100 mol/L Յ3-point MELD variation -3-point difference in 2%; Bil Ն400mol/L Յ7-point MELD variation -Ն3-point difference in 78%. When MELD was Ն25 (mJCr as reference; mean, 30.5 points), MELD variation was greatest: mean, 28 (MELD cJCr), 27.5 (MELD ECr), and 28.4 (MELD JCr) (P Ͻ 0.001). In conclusion, there is poor agreement among different assays for Cr. As Bil concentration rises, there is greater variability in each creatinine measurements and thus greater variability in MELD scores that, this affect prioritization for liver transplantation. Liver Transpl 13: 523-529, 2007.
Sepsis is a common complication of cirrhosis with a high mortality. In this study, we have investigated some of the pathways that may be involved in tissue injury and death. Bile duct-ligated (BDL) cirrhotic and control rats were challenged with lipopolysaccharide (LPS). Sensitivity to LPS was markedly enhanced in the BDL group, and was associated with increased liver injury and mortality. There was a 5-fold constitutive activation of nuclear factor B (NFB) in the liver of BDL rat controls (P F .001), and this was activated further, but to a similar extent, in the liver of both sham and BDL rats after injection of LPS. Plasma tumor necrosis factor ␣ (TNF-␣) increased more markedly in the BDL cirrhotic rats (2,463 ؎ 697 pg/mL in BDL rats versus 401 ؎ 160 pg/mL in the controls at 3 hours; P F .01). Plasma nitrite/nitrate concentrations were increased in the BDL controls at baseline, and increased further after LPS (P F .05), but did not differ from sham controls at 6 hours. Plasma F 2 -isoprostanes increased 6-fold in the cirrhotic rats and 2-fold in the controls (P F .01) indicative of lipid peroxidation. Esterified F 2 -isoprostanes in the liver increased 2-to 3-fold at 1 hour in control and BDL rats, but returned to baseline levels by 3 hours. Esterified F 2 -isoprostanes in the kidney increased by 2-fold in the BDL rats after LPS administration, but remained unchanged in sham controls. We conclude that there is a marked increase in sensitivity to LPS in BDL cirrhotic rats. This is associated with an enhanced TNF-␣ response and increased lipid peroxidation. These may be directly and causally related to mortality. (HEPATOLOGY 1999;30:1198-1205.)Sepsis and associated endotoxemia occur in approximately 40% of hospitalized patients with cirrhosis and is a major cause of death.
Femoral lengthening with the Precice femoral nail achieved excellent functional results with fewer complications and greater patient satisfaction when compared with the LRS system in our patients. Cite this article: Bone Joint J 2016;98-B:1382-8.
Background and aims: Renal failure occurs in approximately 55% of patients with acute liver failure. We have previously shown that plasma endothelin 1 concentrations are elevated in patients with acute liver failure and the hepatorenal syndrome. There are few reported satisfactory animal models of liver failure together with functional renal failure. In this study, a rat model of acute liver failure induced by galactosamine that also develops renal failure was first characterised. This model was used to investigate the hypothesis that endothelin 1 is an important mediator involved in the pathogenesis of renal impairment that occurs in acute liver failure. Methods: Acute liver failure was induced in male Sprague-Dawley rats by intraperitoneal injection of galactosamine together with treatment with the endothelin receptor antagonist Bosentan. Twenty four hour urine collections were made using a metabolic cage. Renal blood flow was measured in anaesthetised animals. Results: This model developed renal failure and liver failure in the absence of any significant renal pathology, and with an accompanying fall in renal blood flow. Plasma concentrations of endothelin 1 were increased twofold following the onset of liver and renal failure (p<0.05), and there was significant upregulation of the endothelin receptor A (ET A ) in the renal cortex (p<0.05). Administration of Bosentan prevented the development of renal failure when given before or 24 hours after the onset of liver injury (p<0.05) but had no effect on liver injury itself, or on renal blood flow. Conclusions: This study demonstrates that this animal model has many of the features needed to be regarded as a model of renal failure that occurs in acute liver failure. The observation that plasma levels of endothelin 1 and ET A receptors are increased and upregulated, and that renal failure is prevented by an endothelin antagonist supports the hypothesis originally put forward that ET A is important in the pathogenesis of renal failure that occurs in patients with acute liver failure.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.