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Biomedical subjects

R A Zager

Publications and source records attributed to R A Zager.

At least 91 records · Page 5Linked to original sources
PubMed1990

Hyperthermia: effects on renal ischemic/reperfusion injury in the rat.

UNLABELLED: Hyperthermia (39.5 degrees C) worsens experimental ischemic acute renal failure (ARF). We assessed whether it does so by affecting the ischemic and/or reperfusion injury phase and if its influence is mediated through changes in kidney ATP content and xanthine oxidase-mediated oxidant stress. Rats were subjected to 25 minutes of renal pedicle occlusion and hyperthermia was imposed during ischemia alone, reflow alone (0 to 30, 30 to 60, and 60 to 90 minutes), ischemia + reflow, or without ischemia. Hyperthermia's effects on ischemic/reperfusion adenylate pools lipid peroxidation (malondialdehyde), and the severity of ARF were assessed in comparison with normothermic ischemic controls. Hyperthermia confined to ischemia profoundly worsened ARF whereas during immediate reflow (0 to 30 minutes) hyperthermia had only a mild ARF-potentiating effect. During late reflow (greater than 30 minutes) or in the absence of ischemia, hyperthermia caused no damage. Hyperthermia had only a brief negative impact on ischemic ATP content, just slightly lowering it during the first 5 minutes of ischemia. Nevertheless, much greater ischemic damage resulted, reflected by increased proximal tubular brush border membrane sloughing at the end of vascular occlusion. Hyperthermia imposed only during reflow did not affect ATP concentrations. Hyperthermia increased end-ischemic purine base concentrations by 10% due to increased ATP degradation. However, reperfusion lipid peroxidation did not result and xanthine oxidase inhibition (by oxypurinol) conferred no protection. CONCLUSIONS: (a) Hyperthermia worsens ARF predominantly by affecting ischemic, not reperfusion, injury; (b) xanthine oxidase is not an important mediator of hyperthermic-ischemic ARF; and (c) hyperthermia has a quantitatively trivial impact on ischemic ATP levels. This suggests that hyperthermia principally worsens ARF by magnifying the consequences of energy depletion (e.g., membrane damage) more than by worsening energy depletion, per se.

Acute Kidney Injury↗
PubMed1989

Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients.

To assess the incidence, risk factors, and course of acute renal failure (ARF) following bone marrow transplantation (BMT), a retrospective analysis of 272 patients receiving transplants at the Fred Hutchinson Cancer Research Center during 1986 was undertaken. The patients were divided into three groups: group 1, hemodialysis requiring ARF; group 2, mild renal insufficiency (doubling of serum creatinine, Scr, but no dialysis); group 3, relatively normal post-BMT renal function (no doubling of Scr). Fifty-three percent of patients at least doubled their Scr (Groups 1 and 2), and 24% required dialysis. The degree of renal functional impairment had a dramatic impact on patient mortality rates (84%, 37%, and 17% in groups 1, 2, and 3, respectively). Jaundice (bilirubin greater than or equal to 2.0 mg/dL), weight gain (greater than or equal to 2.0 kg), amphotericin B use, and a pretransplant Scr greater than or equal to 0.7 mg/dL were independently associated with the subsequent development of dialysis-requiring ARF (P less than 0.001; relative risks, 3.0 to 7.7). Neither aminoglycoside/vancomycin/cyclosporine A use nor acute graft v host disease correlated with the development of ARF. A mismatched graft was a significant risk factor for ARF by univariate but not by multivariate analysis. Within 48 hours before doubling the Scr, 63% of group 1 patients had positive blood cultures and 39% developed hypotension. Of the 26 group 1 patients who had urine Na concentrations measured, 85% had values less than or equal to 40 mEq/L. Autopsy kidney specimens provided no clear explanation for ARF in the vast majority of patients in group 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1989

Pathogenetic mechanisms in experimental hemoglobinuric acute renal failure.

To evaluate mechanisms in hemoglobinuric acute renal failure (ARF) rats were infused with hemoglobin under aciduric or alkalinuric conditions. Aciduric rats developed azotemia, distal heme casts, and proximal tubular cell (PTC) necrosis, whereas alkalinuric rats developed no renal damage. Aciduria converted hemoglobin to met-hemoglobin, which precipitated, forming distal casts and inducing ARF. Hematin formation was not observed. The importance of met-hemoglobin production was indicated by its greater toxicity than hemoglobin during aciduria and by its ability to induce ARF even under alkalinuric conditions. A link between obstructing casts and PTC necrosis was identified; tubular obstruction induced by various mechanisms (met-hemoglobin casts; ureteral ligation; ischemic ARF) increased PTC hemoglobin uptake, producing lysosomal overload (giant endolysosomes) and PTC necrosis. This worsened ischemic ARF despite an otherwise subtoxic hemoglobin dose being used that had no discernible acute renal vasoconstrictive effect. Iron chelation (deferoxamine)/hydroxyl radical scavenger (Na benzoate) therapy did not mitigate this exacerbation of ischemic injury, suggesting a nonoxidant mechanism. We conclude that H is nephrotoxic, particularly when intratubular obstruction facilitates PTC heme uptake. Thus aciduria-induced met-hemoglobin cast formation and concomitant ischemic renal injury predispose to its nephrotoxic effect.

Acute Kidney Injury↗
PubMed1989

Effects of xanthine oxidase inhibition on ischemic acute renal failure in the rat.

To assess the effects of xanthine oxidase (XO) inhibition on ischemic injury, rats were pretreated with oxypurinol (OXY, 5 mg/kg) and subjected to 30 min of bilateral renal artery occlusion. OXY's effect on adenine nucleotide-nucleoside-purine base concentrations was determined at 10 and 30 min of ischemia and during reperfusion (5 and 30 min). To assess whether XO-mediated oxidant stress influences the severity of ischemic acute renal failure (IARF), the effects of 1) OXY pretreatment and 2) hypoxanthine infusion were assessed. During ischemia OXY inhibited XO activity (more than fourfold rise in hypoxanthine-xanthine ratios) and induced quantitatively trivial but significant increases in ATP and total adenine nucleotide concentrations (by 30 min). Increased OXY dosage (15 mg/kg) or allopurinol (40 mg/kg) had no greater effects. At 5 min of reflow, OXY maintained XO inhibition but did not influence adenine nucleotide levels. By 30 min of reflow, 17-20% increments in ATP-total adenine nucleotides resulted. Nevertheless, OXY did not lessen the severity of IARF (assessed by azotemia-histology at 24 h). Hypoxanthine infusion increased end-ischemic hypoxanthine concentrations by 47%, but it did not change the severity of renal damage. Conclusions include 1) OXY-allopurinol induces intrarenal XO inhibition; 2) XO inhibitors slightly increase late ischemic-reperfusion adenine nucleotide concentrations; and 3) neither XO inhibition nor intrarenal hypoxanthine loading alters the severity of IARF, suggesting that XO-mediated oxidant stress is not a critical, consistent mediator of ischemic renal injury.

Acute Kidney Injury↗
PubMed1989

Degree and time sequence of hypothermic protection against experimental ischemic acute renal failure.

The purpose of this study was to assess the degree, time sequence, and biochemical correlates of hypothermic protection against ischemic acute renal failure. Rats subjected to 40 minutes of bilateral renal artery occlusion (RAO) were made mildly hypothermic (32 degrees-33 degrees C, by cold saline peritoneal lavage) during the following time periods: 1) RAO only, 2) reperfusion only (beginning at 0, 15, 30, or 60 minutes after RAO and maintained for 45 minutes), or 3) during and after (0-45 minutes) RAO. Continuously normothermic (37 degrees C) RAO rats served as controls. The control rats developed severe acute renal failure (blood urea nitrogen [BUN], 95 +/- 4 mg/dl; creatinine, 2.2 +/- 0.1 mg/dl; and extensive tubular necrosis at 24 hours). Hypothermia confined to RAO was highly protective (BUN, 33 +/- 5 mg/dl; creatinine, 0.62 +/- 0.07 mg/dl; and minimal necrosis). Hypothermia partially preserved ischemic renal adenylate high-energy phosphate (ATP and ADP), increased AMP and inosine monophosphate concentrations, and lessened hypoxanthine/xanthine buildup (assessed at end of RAO). Hypothermia confined to the reflow period (beginning at 0, 15, and 30 minutes) was only mildly protective (e.g., BUN, 58-63 mg/dl); the degree of protection did not differ according to the time of hypothermic onset. Lowering reflow temperature to 26 degrees C had no added benefit. Hypothermia that started at 60 minutes after RAO conferred no protection. Combining ischemic and postischemic hypothermia abolished all renal failure (assessed at 24 hours). This study offers the following conclusions: Mild hypothermia can totally prevent experimental ischemic acute renal failure. Hypothermia is highly effective during ischemia, and it is mildly protective during early reflow; these benefits are additive. During early reflow, hypothermic protection is not critically time dependent. By 60 minutes of reflow, no effect is elicited; this absence of effect possibly signals completion of the reperfusion injury process. Hypothermia's protective effects may be mediated, in part, by improvements in renal adenine nucleotide content and, possibly, by decreasing postischemic oxidant stress.

Acute Kidney Injury↗
PubMed1989

Minimal risk of chronic renal dysfunction in marrow transplant recipients treated with cyclosporine for 6 months.

To determine whether 6 months of cyclosporine therapy is associated with chronic renal dysfunction, we evaluated serum creatinine concentrations 1 year post-transplant in 82 marrow transplant recipients randomized to receive either cyclosporine (n = 40) or methotrexate (n = 42) as graft-versus-host disease (GVHD) prophylaxis. Nine patients in the methotrexate group were later given cyclosporine as treatment for acute or chronic GVHD (methotrexate----cyclosporine). Cyclosporine prophylaxis was started on the day before marrow infusion, given at full doses until day 50, then gradually tapered and discontinued by day 180. Methotrexate prophylaxis was started on day 1 and given intermittently until day 102. Patients in the cyclosporine and methotrexate----cyclosporine groups had significantly higher mean serum creatinine values during the first 100 days post-transplant than methotrexate-treated patients, but by 1 year mean serum creatinine values were not significantly different between the three groups. Serum creatinine values at 1 year were also not significantly different from baseline values in each of the groups. None of the patients who had their cyclosporine discontinued by day 180 developed chronic renal dysfunction, defined as a doubling of the baseline serum creatinine at 1 year. We conclude that chronic renal dysfunction occurs rarely in marrow transplant recipients treated with 6 months of cyclosporine and when it does occur, it appears to have minimal clinical significance.

Bone Marrow Transplantation↗
PubMed1989

Studies of mechanisms and protective maneuvers in myoglobinuric acute renal injury.

To explore why urine pH affects myoglobin (M)-induced renal injury, rats were infused with M under aciduric (NH4Cl) or alkalinuric (KHCO3) conditions with or without additional solute loading. Acute renal M retention (R) was highly pH dependent (pH 5.77, 68% R; pH 6.45, 49% R; pH 8.0, 28% R), the % R positively affecting the severity of renal injury (azotemia, proximal tubular necrosis, M casts, medullary vascular congestion, assessed 3 and/or 24 hours later). However, nonreabsorbable, nonalkalinizing salts (SO4) equiosmolar to KHCO3 decreased M retention to 21% and produced comparable functional/morphologic protection as HCO3. Equiosmolar reabsorbable salt (NaCl) did not decrease M retention (67%) or confer significant protection. M, when suspended in urine, but not in 0.45% NaCl, was highly acid precipitable (73% versus 10%). Electrophoretic/solubility studies indicated that M, not hematin, precipitated. M infusion did not decrease renal cortical soluble thiol groups (principally glutathione) or raise malondialdehyde concentrations at a time that tubular damage was apparent. Neither deferoxamine nor 2 hydroxyl radical scavengers (dimethylthiouria, Na benzoate) conferred significant functional/morphologic protection. These results indicate that aciduria promotes myoglobinuric-renal injury by acutely trapping M within the kidney, not by causing hematin formation. HCO3 protects by increasing urinary M solubility and by providing nonreabsorbed solute, both facilitating its excretion. Fe-stimulated hydroxyl radical formation does not appear to be necessary for M to cause renal damage.

Acute Kidney Injury↗
PubMed1989

Effects of aging on expression of ischemic acute renal failure in rats.

Ischemic acute renal failure is principally a disease of the elderly, but the effect of aging on renal susceptibility to ischemic damage has not been defined. To address this issue, adolescent (3-4 months), mature (12-13 months), and aged (24-25 months) rats underwent base-line renal functional assessments, and then they were subjected to a standardized ischemic event (37-minute, bilateral renal artery occlusion). The loss of renal function [assessed by azotemia and creatinine clearance, (Ccr)] and the severity of tubular damage (necrosis, casts) were determined 24 hours later. Base-line functional assessments indicated no significant differences in Ccr/100 gm body weight between the groups, but urinary protein excretion increased with age (p less than 0.001). In response to renal artery occlusion, the adolescent, mature, and aged rats lost 59 +/- 4, 82 +/- 4, and 94 +/- 1% of their base-line Ccr (p less than 0.01), respectively. Among the proteinuric rats, no correlation was noted between percent loss Ccr and urinary protein excretion. Despite the large differences in postischemic renal function, the extent of tubular morphologic damage did not differ among the groups. The percent loss Ccr did not correlate with necrosis (r = -0.02) or casts (r = 0.07). Although focal glomerulosclerosis and mild tubular atrophy were noted in the aged kidneys these lesions were minimal to absent in the mature rats. We conclude that aging increases susceptibility to severe ischemic acute renal failure in the rat, an effect that is apparent even during a transition from the adolescent to the mature state. This finding cannot be simply ascribed to increasing proteinuria, a loss of renal functional reserve, or to increased tubular morphologic damage. The data are most consistent with the view that underlying age-related glomerular/hemodynamic changes lead to an exaggerated functional decline in response to ischemic renal injury.

Acute Kidney Injury↗
PubMed1989

An evaluation of the neutrophil as a mediator of in vivo renal ischemic-reperfusion injury.

Previous studies indicated that administration of a monoclonal antibody (MoAb 60.3), which blocks neutrophil adherence to rabbit endothelial cells, prevents ischemic-reperfusion (I-R) injury in multiple extrarenal organs. These findings indicated that the neutrophil can be a critical mediator of I-R tissue damage. To assess whether the neutrophil affects renal I-R injury, MoAb 60.3 was given to rabbits that were then subjected to either 50 minutes or 38 minutes of renal ischemia induced by renal artery occlusion (RAO). The severity of kidney damage was assessed 24 and 48 hours later by blood urea nitrogen and plasma creatinine concentrations and by renal histology. The results were compared with those obtained in time-matched RAO controls. MoAb 60.3 conferred no functional or morphologic protection against either severe or mild ischemic insults. To further evaluate whether neutrophils affect renal I-R injury, rats were depleted of neutrophils (less than 200 cells/mm3) by anti-neutrophil serum administration and then they were subjected to either 37 minutes or 29 minutes of RAO. Neutrophil depletion conferred neither functional nor morphologic protection when compared with time-matched RAO controls. It was concluded that the uniform lack of protection noted in these experiments, despite that two different animals, two different ways of interfering with neutrophil function, and differing severities of ischemic injury were studied, strongly suggests that the neutrophil is not a critical participant in the renal I-R injury process.

Acute Kidney Injury↗
PubMed1988

A focus of tissue necrosis increases renal susceptibility to gentamicin administration.

The purpose of this study was to determine whether a retained focus of necrotic tissue predisposes to aminoglycoside-induced acute renal failure (ARF). Rats were subjected to either (1) 25% liver ligation, creating a focus of ischemic tissue which was left in place; (2) 25% liver resection; or (3) sham liver ligation. Gentamicin, 80 mg/kg bid, was administered for two days after surgery to all three groups. A fourth group was subjected to 25% liver ligation but no gentamicin therapy. Only rats subjected to partial liver ligation plus gentamicin treatment developed ARF, manifested by azotemia (BUN 80 +/- 2; creatinine 1.63 +/- 0.21; mg/dl) and tubular necrosis. This occurred in the absence of any discernible reduction in arterial blood pressure, renal blood flow, excessive weight loss, or ascites formation. The partial liver ligation-gentamicin group had 70% higher renal gentamicin concentrations than the liver resection-gentamicin controls (P = 0.01). To assess whether factors released from necrotic liver might account for these findings, additional rats were infused with: (1) 1 ml of a soluble liver extract alone; (2) 1 ml of liver extract plus gentamicin; or (3) 1 ml of saline plus gentamicin. Only the liver extract/gentamicin group developed ARF (BUN 88 +/- 13; creatinine 1.46 +/- 0.25). This occurred in association with a 110% increase in renal gentamicin uptake (P less than 0.03). In separate experiments, 5 ml liver extract infusions caused ARF (BUN 118 +/- 7; creatinine 2.1 +/- 0.18) without gentamicin treatment. In conclusion, a focus of liver necrosis can predispose to experimental gentamicin nephrotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1988

Gentamicin nephrotoxicity in the setting of acute renal hypoperfusion.

The purpose of this study is to assess interactions between acute renal hypoperfusion and aminoglycoside nephrotoxicity. One hour of renal hypoperfusion (55-60 mmHg; renal blood flow 1.6 +/- 0.13 ml/min) was created in rats by suprarenal partial aortic constriction. Gentamicin, 120 mg/kg, was given at the start of the hypoperfusion period. Rats that either received gentamicin alone or were subjected to hypoperfusion alone served as controls. Hypoperfusion alone induced mild S3 proximal tubular brush-border membrane blebbing, but it caused no enzymuria, azotemia, or tubular necrosis. Gentamicin alone induced no azotemia or tubular necrosis. However, gentamicin injected during hypoperfusion caused severe azotemia (blood urea nitrogen 94 +/- 16; creatinine 1.74 +/- 0.22 mg/dl) and extensive S3 proximal tubular necrosis without affecting renal perfusion. S1 and S2 tubular segments, the major targets of gentamicin toxicity, showed minimal damage. Hypoperfusion increased renal gentamicin uptake, but matching it in control rats induced no renal damage. In conclusion, gentamicin can precipitate hypoperfusion-induced acute renal failure. This effect appears to be due to an S3 cytotoxic effect, which converts sublethal ischemic S3 tubular injury into overt cell necrosis.

Adenine Nucleotides↗
PubMed1988

Evidence against oxidant injury as a critical mediator of postischemic acute renal failure.

The purpose of this study is to confirm previous evidence for reactive oxygen species (ROS) as critical mediators of postischemic renal injury by documenting lipid peroxidation after ischemic-hypoxic insults and by demonstrating that antioxidants confer protection. Renal malondialdehyde (MDA) concentrations, an index of lipid peroxidation, were measured using uncorrected and tissue-chromagen-corrected methods in 1) cortical (C), outer medullary stripe (OMS), inner medullary (IM) whole renal tissues, and C and OMS mitochondria obtained 15 min after in vivo renal artery occlusion (RAO; x 45 min); 2) C, OMS, and IM whole tissues obtained 15 min after completing 45 min of ischemia in an isolated perfused kidney; and 3) isolated proximal tubular cell (PTC) suspensions after 45 min of hypoxia with 15 min of reoxygenation. Despite significant oxygen deprivation-induced injury in each of these systems, no significant rise in MDA concentrations could be documented, with the sole exception of the in vivo IM region (by uncorrected MDA assay only). The latter rise could be attributed to medullary vascular congestion causing a hemoglobin-induced artifact in the MDA assay. Sixty-minute in vivo RAO plus reflow also did not raise MDA. To validate the MDA assay 4.2 mM H2O2 was added to PTC. An abrupt fourfold rise in MDA resulted. Pretreatment of 30- and 45-min RAO rats with two antioxidants (allopurinol or superoxide dismutase) failed to confer functional or morphological protection. We conclude that ROS may not be critical consistent mediators of in vivo postischemic acute renal failure.

Acute Kidney Injury↗
PubMed1988

Hypoperfusion-induced acute renal failure in the rat: an evaluation of oxidant tissue injury.

Reactive oxygen species (ROS) have been reported to be critical cellular mediators of experimental ischemic acute renal failure (ARF). This conclusion is based on observations that in the renal artery occlusion (RAO) model of ARF, antioxidant drugs confer protection and that renal malondialdehyde (MDA) concentrations, an index of lipid peroxidation, rise in the postischemic period. Human ischemic ARF is most often due to hypoperfusion, not to total blood flow interruption. Therefore, the goal of this study was to determine whether ROS also mediate hypoperfusion-induced renal injury. Renal hypoperfusion was induced in rats by suprarenal partial aortic ligation, lowering renal perfusion pressure to 20-25 mm Hg for 45 minutes. Renal MDA concentrations were measured 15 minutes after ligation release. Renal function and morphology were assessed 24 hours after hypoperfusion in control rats and in rats pretreated with antioxidant agents (allopurinol, superoxide dismutase, dimethyl-thiourea, glutathione, and catalase), a majority of which have been shown to lessen RAO-induced ARF. Hypoperfusion caused no rise in renal MDA concentrations (p = 0.54). Control ARF rats developed significant azotemia (blood urea nitrogen 119 +/- 6 mg/dl; creatinine 3.3 +/- 0.37 mg/dl) and widespread tubular necrosis by 24 hours after surgery. None of the antioxidants, administered singly or in combination, lessened the ischemic damage. Therefore, renal MDA concentrations do not rise in hypoperfusion ARF, and antioxidants do not confer protection. This indicates that previous evidence for ROS as mediators of ischemic renal injury is restricted to the RAO model of ARF, which does not closely simulate most human ischemic renal injury.

Acute Kidney Injury↗
PubMed1988

Precipitable tissue proteins can cause experimental acute renal failure.

UNLABELLED: A previous investigation demonstrated that intravenous infusion of a saline-liver extract into rats causes acute renal failure (ARF), manifested by severe azotemia, extensive cast formation, and patchy tubular necrosis. The purpose of the present study was to explore its pathogenesis. Histologic assessments of rat kidneys made 1.5 hours after liver extract infusion demonstrated eosinophilic material within glomerular capillaries, Bowman's space, and proximal tubular lumina, distal nephron cast formation, and tubular dilation without evidence of tubular necrosis. Renal blood flow at this time was normal but the rats were anuric. Assessments made 24 hours after liver extract infusion demonstrated persisting ARF (blood urea nitrogen, 132 +/- 8; creatinine, 2.54 +/- 0.19 mg/dl), profound cast deposition almost exclusively in the inner medulla/papilla, and the appearance of patchy proximal tubular necrosis. Sephacryl S200 fractionation and 10% polyacrylamide gel electrophoresis of liver extract showed high and low molecular weight proteins (less than 30,000). Proteins in both regions demonstrated prominent acid precipitability (pH 4.5) and autoaggregation (at 37 degrees C). Trace amounts of spontaneously precipitated protein recovered from urine during liver extract infusion demonstrated a predominance of low molecular weight proteins by polyacrylamide gel electrophoresis. Infusing rats with filterable low molecular weight proteins (cytochrome c, ribonuclease, myoglobin) without autoaggregation/acid precipitation characteristics or liver extract made devoid of precipitable proteins failed to induce ARF. However, infusing a kidney extract containing acid precipitating/autoaggregating proteins caused inner medullary/papillary cast formation and ARF. CONCLUSION: normal parenchymal tissues contain proteins which can undergo glomerular filtration and which can spontaneously aggregate under conditions which exist in the distal nephron. If released into the circulation, or if shed from tubular cells into lumina after nephrotoxic or ischemic renal injury, they could help to induce intratubular obstruction and ARF.

Acute Kidney Injury↗
PubMed1987

Exogenous creatinine clearance accurately assesses filtration failure in rat experimental nephropathies.

The purpose of this study was to determine whether creatinine clearance (Ccr), determined under conditions of exogenous creatinine infusion, accurately reflects glomerular filtration rate (GFR) in the rat. Normal rats and rats with either glomerulopathy (nephrotoxic serum nephritis, adriamycin nephropathy), ablative nephropathy, or acute renal failure (ischemic, HgCl2) were subjected to simultaneous Ccr and inulin clearance (Cin) determinations at a time that plasma creatinine concentrations were maintained at 10 to 20 mg/dL by exogenous creatinine infusion. Cin ranged from 0.02 to 2.49 mL/min, and a nearly perfect correlation with Ccr (r = .997) was obtained. Excellent correlations between Ccr and Cin were found in each of the individual study groups. When the rats were subdivided into groups according to their level of renal function (Cin greater than 1.5 mL/min; Cin 0.5 to 1.49 mL/min; Cin 0.02 to 0.49 mL/min), excellent correlations between Cin and Ccr were still observed (r = .93, .97, and .97, respectively). We concluded that exogenous Ccr accurately reflects GFR in the rat over the entire range of renal function and in a wide variety of experimental nephropathies. Given the simple methodology, exogenous Ccr could have substantial research application for assessing degrees of excretory function in experimental renal disease.

Animals↗
PubMed1987

Partial aortic ligation: a hypoperfusion model of ischemic acute renal failure and a comparison with renal artery occlusion.

Ischemic acute renal failure (ARF) in humans typically results from hypoperfusion, not total blood flow interruption. However, experimental studies of ischemic ARF have relied on total blood flow cessation models because no reliable hypoperfusion model has been described. Therefore, the goal of this study was to develop a hypoperfusion model of ischemic ARF and then to contrast it to a blood flow cessation model (renal artery occlusion). Rats were uninephrectomized, and then temporary (30 or 45 minute) partial aortic ligation (PAL) was created just above the left renal artery, yielding a renal perfusion pressure of 15 to 20 mm Hg and a renal blood flow of 0.1 to 0.2 ml/min. The severity of renal injury was assessed 24 hours later. Azotemia (30-minute PAL: BUN 47 +/- 5 mg/dl; 45-minute PAL: 118 +/- 11 mg/dl), depressed inulin clearances, and extensive pars recta proximal tubular necrosis resulted. Comparing 30 minutes of PAL with 30 minutes of renal artery occlusion revealed far less severe ischemic adenosine triphosphate depletion (P less than 0.001), less azotemia (P less than 0.05), less medullary vascular congestion (P less than 0.05), and less cast formation (P less than 0.05) with PAL. However, both models induced comparable degrees of tubular necrosis, oxidant tissue stress (as assessed by oxidized-reduced glutathione tissue assay), and post-ischemic adenosine triphosphate depletion. Both similarities and differences exist between hypoperfusion and blood flow cessation-induced experimental ARF. The difference indicate that blood flow cessation models may not closely simulate clinical ischemic renal injury.

Acute Kidney Injury↗
PubMed1987

Low molecular weight proteinuria exacerbates experimental ischemic renal injury.

To determine whether tubular reabsorption of low molecular weight proteins (LMWPs) alters ischemic tubular injury, rats were infused with 25 mg of lysozyme (isoelectric point (pI) 11.3), cytochrome C (pI 10.6), ribonuclease (pI 8.7), or myoglobin (pI 7.0), and during this time 25 minutes of bilateral renal artery occlusion (RAO) was induced. RAO control rats received either saline or 25 mg of albumin. Renal injury was assessed 24 hours later by blood urea nitrogen, creatinine, and histology. Lysozyme, ribonuclease, and myoglobin each exacerbated ischemic damage (increased tubular necrosis, cast formation, azotemia), but to comparable degrees (e.g., blood urea nitrogen range 75 +/- 8 to 100 +/- 5 mg/dl versus controls, 29 +/- 2 to 36 +/- 7; p less than 0.01). Rendering lysozyme anionic (pI 4.5) by succinylation did not diminish its acute renal failure-potentiating effect. Cytochrome C which is freely filtered but poorly reabsorbed had a minimal impact on the ischemic process. Infusion of LMWPs did not alter blood pressure, renal blood flow, or induce renal injury in the absence of RAO. During a sublethal ischemic event (10 minutes of RAO) LMWP infusion exacerbated proximal tubular luminal membrane damage before an adverse effect on other critical determinants of cell integrity were apparent (adenine nucleotide pools, oxidant stress). We conclude that endocytic LMWP reabsorption by proximal tubules can exacerbate superimposed ischemic tubular necrosis independent of any direct nephrotoxic protein effect. This action is not influenced by protein isoelectric point and appears to be mediated by a primary intensification of ischemic luminal membrane damage.

Animals↗