Increased renal glomerular endothelin-1 release in gentamicin-induced nephrotoxicity.
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Gentamicin-induced acute renal failure is characterized by a decrease in renal plasma flow and creatinine clearance. Endothelins (ET) are potent renal vasoconstrictors. The aim of this work is to assess the role of ET-1 in gentamicin-induced renal failure. Renal glomerular release of ET-1 was measured in rats with gentamicin-induced nephrotoxicity (100 mg/kg/day, s.c. for 2, 4 or 6 days). Glomeruli were isolated and incubated for 24 h in RPMI-1640. Glomerular supernatant and plasma concentration of ET-1 were measured by RIA. Renal failure was assessed by insulin, para-aminohippuric and creatinine clearance and histological studies. Gentamicin induced a dose number-dependent increase in plasma creatinine and a decrease in creatinine clearance. This was accompanied by a marked decrease in inulin and para-aminohippuric acid clearance, as well as by a marked tubular necrosis, without alterations in glomerular structures. Plasma ET-1 concentration and glomerular ET-1 release were also increased in gentamicin-treated rats. When 10-5 M gentamicin was added to control glomeruli, ET-1 production was not modified (36.4 +/- 2.2 vs. 35.2 +/- 1.7 pg/ml/24 h). All these results suggest that elevated ET-1 plasma levels and increased glomerular release of ET-1 could mediate, at least in part, the decrease in glomerular filtration rate observed in gentamicin-induced ARF. (+info)
Prostaglandin E1: a new agent for the prevention of renal dysfunction in high risk patients caused by radiocontrast media? PGE1 Study Group.
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BACKGROUND: Acute renal failure following the administration of radiocontrast media (RCM) is a complication found especially in patients with impaired renal function. Within the limits of a pilot study, the objective was to (a) show the effectiveness and compatibility of prostaglandin E(1) (PGE(1)=Alprostadil) in preventing acute renal failure in patients with elevated levels of serum creatinine and (b) to identify the most appropriate PGE(1)-dose. METHODS: 130 patients with renal impairment (serum creatinine >/=1.5 mg/dl) were included in the study prior to intravascular RCM injection. The patients received one of three different doses of PGE(1) (10, 20, or 40 ng/kg bodyweight/min) or placebo (physiologic sodium chloride solution) intravenously over a time period of 6 h (beginning 1 h prior to RCM application). Serum creatinine was measured 12, 24, and 48 h post RCM-application and creatinine clearance was determined with two 12 h collection periods, as well as one 24 h collection within 48 h post RCM administration. Adverse events during PGE(1) administration were recorded. RESULTS: In the placebo group, the mean elevation of serum creatinine was markedly higher (0.72 mg/dl) 48 h after RCM administration compared with the three PGE(1) groups (0.3 mg/dl in the 10 ng/kg/min group, 0. 12 mg in the 20 ng/kg/min group, and 0.29 mg/dl in the 40 ng/kg/min group). No clinically relevant changes were seen regarding the creatinine clearance in the four groups examined. CONCLUSIONS: Results from this pilot-study suggest that intravenous PGE(1) may be used efficaciously and safely to prevent RCM-induced renal dysfunction in patients with pre-existing impaired renal function. (+info)
Lack of renoprotective effects of dopamine and furosemide during cardiac surgery.
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Because development of acute renal failure is one of the most potent predictors of outcome in cardiac surgery patients, the prevention of renal dysfunction is of utmost importance in perioperative care. In a double-blind randomized controlled trial, the effectiveness of dopamine or furosemide in prevention of renal impairment after cardiac surgery was evaluated. A total of 126 patients with preoperatively normal renal function undergoing elective cardiac surgery received a continuous infusion of either "renal-dose" dopamine (2 microg/kg per min) (group D), furosemide (0.5 microg/kg per min) (group F), or isotonic sodium chloride as placebo (group P), starting at the beginning of surgery and continuing for 48 h or until discharge from the intensive care unit, whichever came first. Renal function parameters and the maximal increase of serum creatinine above baseline value within 48 h (deltaCrea(max)) were determined. The increase in plasma creatinine was twice as high in group F as in groups D and P (P < 0.01). Acute renal injury (defined as deltaCreamax) >0.5 mg/dl) occurred more frequently in group F (six of 41 patients) than in group D (one of 42) and group P (zero of 40) (P < 0.01). (The difference between group D and group P was not significant.) Creatinine clearance was lower in group F (P < 0.05). Two patients in group F required renal replacement therapy. The mean volume of infused fluids, blood urea nitrogen, serum sodium, serum potassium, and osmolar- and free-water clearance was similar in all groups. It was shown that continuous infusion of dopamine for renal protection was ineffective and was not superior to placebo in preventing postoperative dysfunction after cardiac surgery. In contrast, continuous infusion of furosemide was associated with the highest rate of renal impairment. Thus, renaldose dopamine is ineffective and furosemide is even detrimental in the protection of renal dysfunction after cardiac surgery. (+info)
A trial of thyroxine in acute renal failure.
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A trial of thyroxine in acute renal failure. BACKGROUND: Acute renal failure (ARF) remains a serious medical problem with a high mortality rate. Efforts to shorten the course of ARF might reduce this mortality. Since thyroxine has been shown in experimental models to shorten the course of ARF, we designed a trial to determine if a defined course of thyroxine would alter the course or change the mortality of clinical ARF. METHODS: A prospective, randomized, placebo-controlled, double-blind trial of thyroxine was carried out in patients with ARF. End points were the percentage requiring dialysis, the percentage recovering renal function, time to recovery, and mortality. RESULTS: Fifty-nine patients were randomized to receive either thyroxine or placebo. The groups were well matched in terms of basal and entry creatinines, age, sex, APACHE II scores at entry, and percentage oliguric. Baseline thyroid functions, including T3, T4, rT3, and thyroid stimulating hormone (TSH) levels, were equal between the two groups and typical of patients with euthyroid sick syndrome. Thyroxine resulted in a progressive and sustained suppression of TSH levels in the treated group, but had no effect on any measure of ARF severity. Mortality was higher in the thyroxine group than the control group (43 vs. 13%) and correlated with suppression of TSH. CONCLUSIONS: In contrast to the beneficial effects seen in experimental ARF, thyroxine has no effect on the course of clinical ARF and could have a negative effect on outcome through prolonged suppression of TSH. Critically ill euthyroid sick patients should not be replaced with thyroid hormone. (+info)
Rhabdomyolysis and acute renal failure resulting from alcohol and drug abuse.
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Rhabdomyolysis is a common cause of acute renal failure (ARF) associated with drug misuse. Abuse of the gel formulation of temazepam has been a particular problem in the West of Scotland. We performed a retrospective review of dialysis-dependent ARF from rhabdomyolysis and drug misuse in the West of Scotland, 1986-1997. We identified 76 patients, of whom 87% were male. Seventeen cases occurred in the first 6 years, compared with 59 in the subsequent 6 years. Median age was 32. Thirty cases followed intravenous drug misuse, 46 followed oral drug misuse. The substances most frequently misused were alcohol (54%), heroin (24%) and parenteral temazepam (17%). The temazepam cases all followed the introduction of the gel formulation. Three out of 4 patients requiring limb amputation had injected temazepam. Of intravenous drug misusers tested, 72% were hepatitis-C-positive. Some 43% of patients had deprivation scores in the worst category. ARF due to rhabdomyolysis from substance misuse is increasing in our area. Alcohol is frequently responsible. The introduction of the gel formulation of temazepam has contributed to the increase. Those at risk in this study were young, male, had a high incidence of hepatitis C and lived in the most deprived areas. (+info)
Blocking P-selectin protects from ischemia/reperfusion-induced acute renal failure.
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Acute renal failure (ARF) in response to ischemia-reperfusion is thought to be associated with neutrophil infiltration. Neutrophil recruitment depends on adhesion molecules, including P-selectin. Our study sought to characterize the role of P-selectin in ischemia-reperfusion (I/R) -induced acute renal failure (ARF). In wild-type (wt) and P-selectin-deficient (P-/-) mice (both C57BL/6), ARF was induced by 32 min bilateral renal ischemia, followed by reperfusion (I/R). Wt showed a 12- and 20-fold increase in creatinine at 24 and 48 h after I/R, respectively. Similar changes were seen in blood urea nitrogen (BUN). By contrast, in P-/- creatinine and BUN increased only moderately (fourfold over sham). In wt, renal myeloperoxidase activity, indicating neutrophil infiltration, peaked after 24 h (19-fold over sham). This was significantly attenuated in P-/- (fivefold over sham). Western blot analysis revealed maximum P-selectin expression 12 h after I/R in wt. Immunostaining detected P-selectin in glomerular endothelium and in platelets adherent in glomerular and peritubular vessels. Postischemic injection of P-selectin antibody at 10 min after reperfusion, but not isotype control antibody, protected wt from ARF similar to the protection seen in P-/-. We conclude that blocking P-selectin even after onset of reperfusion protects mice from I/R-induced ARF, suggesting potential therapeutic strategies aimed at blocking P-selectin. (+info)
An in vivo approach showing the chemotactic activity of leukotriene B(4) in acute renal ischemic-reperfusion injury.
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Neutrophil migration protects the body against foreign invasion. Sequestration and activation of neutrophils, however, require stringent regulation because they may also cause tissue damage by the release of lysosomal enzymes and reactive oxygen species. The activity of various chemoattractants [e.g., leukotriene B(4) (LTB(4)), interleukin-8, and complements] has been documented by in vitro assays, whereas in vivo data have been limited mostly to histology. To examine in an in vivo model the chemotactic activity and subsequent tissue infiltration and the role of a specific chemoattractant, LTB(4), we used a rat renal ischemia-reperfusion injury model. Fluorescence-labeled Chinese hamster ovary (CHO) cells stably expressing the LTB(4) receptor (CHO-BLT) were able to accumulate along with neutrophils in the postischemic kidney, in contrast to vector control CHO cells. Furthermore, LTB(4) antagonists that protect against the decrease in renal function and diminish the tissue myeloperoxidase activity also led to the marked decrease in the number of CHO-BLT cells and neutrophils. Thus, LTB(4) alone appears sufficient to cause cells to migrate into postischemic tissues, and its dominant role in reperfusion injury has been demonstrated. The utilization of transfectants to pinpoint the role of LTB(4) in these in vivo experiments suggests their potential use with other ligands and/or in other pathological conditions. (+info)
Acute renal failure. II. Experimental models of acute renal failure: imperfect but indispensable.
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Acute renal failure (ARF) due to ischemic or toxic renal injury, a clinical syndrome traditionally referred to as acute tubular necrosis (ATN), is a common disease with a high overall mortality of approximately 50%. Little progress has been made since the advent of dialysis more than 30 years ago in improving this outcome. During this same period, a considerable amount of basic research has been devoted to elucidating the pathophysiology of ATN. The ultimate goal of this research is to facilitate the development of therapeutic interventions that either prevent ARF, ameliorate the severity of tubular injury following an acute ischemic or toxic renal insult, or accelerate the recovery of established ATN. This research endeavor has been highly successful in elucidating many vascular and tubular abnormalities that are likely to be involved in ischemic and toxic ARF. This information has led to impressive advances in the development of a number of different pharmacological interventions that are highly effective in ameliorating the renal dysfunction in animal models of ARF. Although these developments are exciting and promising, enthusiasm of investigators involved in this endeavor has been tempered somewhat by the results of a few recent clinical studies of patients with ATN. These trials, designed to examine the efficacy in humans of some of the interventions effective in animal models of ARF, have resulted in little or no benefit. This is therefore an important time to reevaluate the approaches we have taken over the past three to four decades to develop new and effective treatments for ATN in humans. The major goals of this review are 1) to evaluate the relevance and utility of the experimental models currently available to study ischemic and toxic renal injury, 2) to suggest novel experimental approaches and models that have the potential to provide advantages over methods currently available, 3) to discuss ways of integrating results obtained from different experimental models of acute renal injury and of evaluating the relevance of these findings to ATN in humans, and 4) to discuss the difficulties inherent in clinical studies of ATN and to suggest how studies should be best designed to overcome these problems. (+info)