Experimental Models of Acute Renal Failure and Erythropoietin: What Evidence of a Direct Effect?

Renal Failure ◽  
2007 ◽  
Vol 29 (3) ◽  
pp. 379-386 ◽  
Author(s):  
Alessio Sturiale ◽  
Susanna Campo ◽  
Eleonora Crascì ◽  
Carmela Aloisi ◽  
Michele Buemi
Keyword(s):  
Renal Failure ◽  
Acute Renal Failure ◽  
Direct Effect ◽  
Experimental Models

Acute renal failure. II. Experimental models of acute renal failure: imperfect but indispensable

2000 ◽  
Vol 278 (1) ◽  
pp. F1-F12 ◽  
Keyword(s):  
Renal Failure ◽  
Acute Renal Failure ◽  
Animal Models ◽  
Renal Injury ◽  
Clinical Studies ◽  
Basic Research ◽  
Experimental Models ◽  
Clinical Syndrome ◽  
Therapeutic Interventions ◽  
Common Disease

Acute renal failure (ARF) due to ischemic 1 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 ∼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.

Acute renal failure. III. The role of growth factors in the process of renal regeneration and repair

2000 ◽  
Vol 279 (1) ◽  
pp. F3-F11 ◽  
Keyword(s):  
Renal Failure ◽  
Acute Renal Failure ◽  
Growth Factors ◽  
Experimental Models ◽  
Future Research ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Renal Regeneration ◽  
General Studies

This review, which is the final installment in a series devoted to controversial issues in acute renal failure (ARF) (3, 47), will examine available information regarding the role of growth factors in ARF. In general, studies in this area have fallen into two broad categories: 1) those that have examined the renal expression of genes encoding growth factors or transcriptional factors associated with the growth response that is induced after ARF, and 2) those that have examined the efficacy of exogenously administered growth factors in accelerating recovery of renal function in experimental models of ARF. Despite the vast amount of information that has accumulated in these two areas of investigation, our understanding of the mechanisms involved in the process of regeneration and repair after ARF, and the role of growth factors in this response, remains rudimentary. This overview, contributed to by a number of experts in the field, is designed to summarize present knowledge and to highlight potentially fertile areas for future research in this area.

Current concepts on the pathophysiology of acute renal failure

1978 ◽  
Vol 234 (3) ◽  
pp. F171-F181 ◽  
Author(s):  
J. H. Stein ◽  
M. D. Lifschitz ◽  
L. D. Barnes
Keyword(s):  
Renal Failure ◽  
Blood Flow ◽  
Acute Renal Failure ◽  
Volume Expansion ◽  
Filtration Rate ◽  
Experimental Models ◽  
Tubular Epithelium ◽  
Norepinephrine Infusion ◽  
Glycerol Injection ◽  
Cellular Integrity

In the pase decade, several experimental models of acute renal failure (ARF) have been evaluated with micropuncture and hemodynamic techniques. Five of these models have been most extensively studied: glycerol injection, renal artery clamping, intrarenal norepinephrine infusion, uranyl nitrate, and mercuric chloride administration. In the first three models, renal ischemia is the initiating insult, whereas in the two nephrotoxic models a direct effect of the agent on cellular integrity is also seemingly operative. In all of these models, renal blood flow 24--48 h after the initial insult either spontaneously returns to normal or can be elevated to this level with volume expansion but without restoration of the glomerular filtration rate. Therefore, the maintenance of ARF in these various models is due to other factors, which include tubular obstruction, leakage of filtrate across damaged tubular epithelium, and a decrease in the glomerular capillary ultrafiltration coefficient. In a given model, one or all three of these alterations may be present. Although these various models may not be completely analogous to the clinical setting, they have provided powerful tools for the study of ARF and their use has greatly increased our knowledge in this field.

Hemoglobin- and myoglobin-induced acute renal failure in rats: role of iron in nephrotoxicity

1988 ◽  
Vol 255 (3) ◽  
pp. F539-F544 ◽  
Author(s):  
M. S. Paller
Keyword(s):  
Lipid Peroxidation ◽  
Renal Failure ◽  
Acute Renal Failure ◽  
Renal Dysfunction ◽  
Critical Role ◽  
Iron Chelator ◽  
Experimental Models ◽  
Inulin Clearance ◽  
Glycerol Injection ◽  
Malondialdehyde Content

In ischemic acute renal failure oxygen free radicals may mediate injury. In addition, iron appears to play a critical role in hydroxyl radical formation and lipid peroxidation during reperfusion of ischemic kidneys. To determine whether iron may play a similar role in pigment (heme protein)-induced acute renal failure, we studied the effects of the iron chelator deferoxamine in two experimental models of pigment-induced acute renal failure, intramuscular glycerol injection and intravenous hemoglobin infusion without and with concurrent ischemia in the rat. Intramuscular injection of 50% glycerol (5 ml/kg) caused inulin clearance to fall to 0.13 +/- 0.03 (SE) ml/min (normal value, 1.0–1.2 ml/min). Continuous infusion of deferoxamine beginning at the time of glycerol injection significantly attenuated this renal dysfunction. Deferoxamine-treated animals had an inulin clearance of 0.37 +/- 0.06 ml/min (P less than 0.01). Glycerol injection was also associated with significant lipid peroxidation, measured as renal malondialdehyde content. Deferoxamine-treated glycerol-injected rats had renal malondialdehyde content not significantly different from control animals. In another model of heme pigment-induced renal injury, hemoglobin was infused to produce hemoglobinuria. Inulin clearance 1 h after hemoglobin infusion was significantly reduced to 0.84 +/- 0.5 ml/min (P less than 0.025). Infusion of deferoxamine after hemoglobin prevented the hemoglobin-induced decrease in inulin clearance. Thirty minutes of renal ischemia followed by infusion of hemoglobin resulted in more severe renal dysfunction with inulin clearance of 0.54 +/- 0.08 ml/min. Deferoxamine infused at the time of reperfusion attenuated the fall in glomerular filtration rate after ischemia and hemoglobin infusion:inulin clearance 1.04 +/- 0.07 (P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute renal failure after whole body ischemia is characterized by inflammation and T cell-mediated injury

2003 ◽  
Vol 285 (1) ◽  
pp. F87-F94 ◽  
Author(s):  
Melissa J. Burne-Taney ◽  
Julia Kofler ◽  
Naoko Yokota ◽  
Myron Weisfeldt ◽  
Richard J. Traystman ◽  
...  
Keyword(s):  
Renal Failure ◽  
Acute Renal Failure ◽  
T Cell ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Experimental Models ◽  
Whole Body ◽  
Tubular Injury ◽  
Renal Tubular ◽  
Deficient Mice

Acute renal failure (ARF) commonly occurs after whole body ischemia. Most experimental models of ARF have relied on the isolated renal artery clamping model; however, there is a pressing need to develop and understand the pathogenesis of new models with more “clinical relevance.” We evaluated a new murine model of ARF after whole body ischemia reperfusion injury (WBIRI). WBIRI was induced by an infusion of potassium chloride and a cardiac arrest period of 10 min. Resuscitation was achieved by cardiac compressions, ventilation, epinephrine, and fluids. WBIRI leads to a significant increase in serum creatinine (SCr) and renal tubular injury by 24 h. Renal myeloperoxidase (MPO) levels increased at 24 h after WBIRI. Increased expression of the proinflammatory genes, ICAM-1 and IL-6, was also observed in the kidney following WBIRI. On the basis of recent data that T cells are important mediators of isolated renal IRI, WBIRI was evaluated in T cell-deficient nu/nu mice. T cell-deficient mice had a significantly reduced rise in SCr and decreased tubular injury compared with wild-type mice. T cell-deficient mice had a decrease in ICAM-1 expression after WBIRI, but no decrease in renal MPO. This study describes a new, clinically relevant, model of ARF after WBIRI in mice and identifies the T cell as an important mediator of renal injury following WBIRI. Reduced ICAM-1 expression may provide a mechanism for this involvement.

The Renin-Angiotensin System in Acute Renal Failure in Rats

1974 ◽  
Vol 47 (1) ◽  
pp. 79-88 ◽  
Author(s):  
P. G. Matthews ◽  
T. O. Morgan ◽  
C. I. Johnston
Keyword(s):  
Renal Failure ◽  
Acute Renal Failure ◽  
Mercuric Chloride ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Experimental Models ◽  
Active Immunization ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Plasma Angiotensin

1. Serial changes in plasma renin activity and plasma angiotensin levels were followed in rats during acute renal failure induced by mercuric chloride or glycerol. 2. During mercuric chloride-induced acute renal failure there were transitory large increases in plasma renin and angiotensin. In contrast, rats with acute renal failure produced by glycerol had a reduction in plasma renin and angiotensin levels at 1 h, after which the levels returned to control values. 3. There was no correlation between the systemic changes in plasma renin and angiotensin and the mortality from or severity of the renal failure. 4. Passive or active immunization of rats to angiotensin afforded no protection against renal failure associated with either glycerol or mercuric chloride. 5. It is concluded that the renin-angiotensin system plays no direct systemic vasoconstrictor role in the production of acute renal failure in these experimental models in rats.

The role of adenosine in HgCl2-induced acute renal failure in rats

1990 ◽  
Vol 258 (6) ◽  
pp. F1554-F1560 ◽  
Author(s):  
N. Rossi ◽  
V. Ellis ◽  
T. Kontry ◽  
S. Gunther ◽  
P. Churchill ◽  
...  
Keyword(s):  
Renal Failure ◽  
Acute Renal Failure ◽  
Adenosine Receptor ◽  
Maintenance Phase ◽  
Experimental Models ◽  
Inulin Clearance ◽  
Protective Effects ◽  
Hemodynamic Changes ◽  
Initiation Phase

It has been proposed that adenosine mediates the renal hemodynamic changes in acute renal failure (ARF) and that these changes are pathogenic in reducing glomerular filtration rate. Consistently, adenosine-receptor antagonists such as theophylline have been shown to have protective effects in several experimental models of ARF. The present experiments were designed to explore the potential role of adenosine in HgCl2-induced ARF in rats. In isolated perfused rat kidneys, HgCl2 increased adenosine production and induced a concentration-dependent vasoconstriction. However, the vasoconstriction was unrelated to adenosine production and was not antagonized by theophylline. During the initiation phase of HgCl2-induced ARF in intact rats (first 4 h after injection), theophylline failed to reverse the reduction in inulin clearance, and this failure could not be attributed to a loss of vascular responsiveness to adenosine, since N6-cyclohexyladenosine, a receptor agonist, produced a further reduction in inulin clearance. Furthermore, theophylline actually had deleterious effects during the maintenance phase of HgCl2-induced ARF in intact unanesthetized rats, as evidenced by higher mean serum creatinine values in theophylline-injected rather than in saline-injected rats, on both the second and third days after HgCl2 injection. Therefore HgCl2 acutely increases renal adenosine production, but increased adenosine does not mediate acute HgCl2-induced renal vasoconstriction, and adenosine-receptor antagonism does not have protective effects during the initiation or the maintenance phases of HgCl2-induced ARF in rats. These results provide no support for the hypothesis that increased adenosine mediates the hemodynamic changes in HgCl2-induced ARF.

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