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Biomedical subjects

R A Zager

Publications and source records attributed to R A Zager.

At least 109 records · Page 6Linked to original sources
PubMed1986

Body temperature: an important determinant of severity of ischemic renal injury.

To assess the effects of body temperature on renal susceptibility to ischemic injury, rats were rendered acutely hypothermic (90-93 degrees F), normothermic (98-99 degrees F), or hyperthermic (101-103 degrees F) with a heat-controlled surgical board and then were subjected to 25 min of bilateral renal artery occlusion (RAO). Renal high-energy phosphates, their degradation products, and nonprotein sulfhydryl (NPSH) content were assessed at selected times during the peri-ischemic period. The severity of acute renal failure (ARF) was determined for 48 h following RAO by blood urea nitrogen (BUN) and plasma creatinine determinations and by renal histology. Ischemic ATP, ADP, AMP, GTP, GDP, UTP, and NAD levels and postischemic NPSH levels (15 min reflow) inversely correlated with temperature (P less than 0.001). BUN, creatinine concentrations (at 24 and 48 h), and histological injury (at 48 h) directly correlated with temperature (P less than 0.01). Hyperthermia in the absence of RAO had no demonstrable adverse renal effects. We conclude that hyperthermia potentiates ischemic renal injury, whereas hypothermia confers protection. These effects are associated with, and may be influenced by, temperature-induced changes in renal high-energy phosphate availability and oxidant stress during the ischemic/postischemic period.

Adenine Nucleotides↗
PubMed1986

Escherichia coli endotoxin injections potentiate experimental ischemic renal injury.

UNLABELLED: The purpose of this study was to assess the influence of Escherichia coli endotoxin on the evolution of ischemic acute renal failure (ARF). Rats were subjected to 25 min of bilateral renal artery occlusion (RAO) plus subcutaneous/intraperitoneal injections of either boiled E. coli or purified E. coli endotoxin (1.5 mg). Boiling the E. coli renders them nonviable but leaves endotoxin intact. Ischemic controls were injected with saline. The E. coli injections exacerbated ischemic ARF, doubling the degree of azotemia and increasing the extent of tubular necrosis and cast formation. This occurred without an adverse effect on renal blood flow or blood pressure during the initiation phase or maintenance phase of the ARF. Endotoxin tolerant rats were totally protected against the E. coli-ARF potentiating effect. Neither Staphylococcus aureus nor E. coli with denatured endotoxin adversely affected ischemic injury. Purified E. coli endotoxin reproduced the E. coli-ARF potentiating action. Neither E. coli nor purified endotoxin induced azotemia in the absence of renal ischemia. CONCLUSION: E. coli endotoxin can exacerbate ischemic renal injury without compromising renal hemodynamics. This action appears to be mediated by an adverse effect of endotoxin on critical subcellular determinants of ischemic tissue injury.

Acute Kidney Injury↗
PubMed1986

Gentamicin and gram-negative bacteremia. A synergism for the development of experimental nephrotoxic acute renal failure.

To explore whether bacteremia potentiates gentamicin nephrotoxicity, we injected rats with either 1 X 10(9) Escherichia coli (E. coli), Pseudomonas aeruginosa, or Staphylococcus aureus, and then gave them gentamicin, 100 mg/kg. Renal injury was assessed over the next 24-48 h. Staphylococcus/gentamicin or gentamicin alone induced no renal injury. However, E. coli/gentamicin and Pseudomonas/gentamicin caused acute renal failure (severe azotemia; tubular necrosis; cast formation). This effect was not due to acute reductions in arterial blood pressure or renal blood flow, it could be reproduced by substituting nonviable for viable gram-negative organisms, and it was associated with increased renal gentamicin uptake. E. coli without gentamicin induced only mild azotemia and no tubular necrosis. Endotoxin-tolerant rats were significantly protected against the E. coli/gentamicin nephrotoxic interaction. We conclude that gram-negative bacteremia and gentamicin exert synergistic nephrotoxicities; and that this effect is mediated, at least in part, by endotoxin and in part by increased renal gentamicin uptake.

Acute Kidney Injury↗
PubMed1986

Alterations of intravascular volume: influence on renal susceptibility to ischemic injury.

The purpose of this investigation was to test whether alterations of intravascular volume change renal susceptibility to ischemic injury. Acute volume depletion (2% body weight; by furosemide injection or by hemorrhage) or volume expansion (10% body weight; by saline infusion) was induced in Sprague-Dawley rats. The effects of these interventions on renal blood flow (RBF), mean arterial blood pressure (MAP), glomerular filtration rate (GFR), and renal adenine nucleotide content were assessed by comparison with values observed in euvolemic control rats. Volume-depleted, volume-expanded, and euvolemic control rats were also subjected to 25 minutes of bilateral renal artery occlusion (RAO). The severity of ischemic injury was assessed 24 hours later (by determination of GFR, blood urea nitrogen, creatinine, and histology). Before RAO, the volume-depleted rats had significant reductions in GFR (33%), MAP (20% to 45%), and RBF (52% to 72%), but renal adenosine triphosphate (ATP) content was totally preserved. Both groups of volume-depleted rats had normal susceptibility to RAO, compared with the euvolemic controls. Before RAO, volume expansion had no significant effect on GFR, MAP, or RBF, but it decreased renal ATP content by 21%. In addition, volume expansion significantly exacerbated the ATP depletion that occurred both during and after RAO. Nevertheless, the volume-expanded rats were almost totally protected against ischemia. It is concluded that the kidney can tolerate severe volume depletion without apparent deterioration in tubular cell energetics or a change in renal susceptibility to superimposed ischemic injury. Acute volume expansion can protect against ischemic injury, despite lowering renal ATP content.

Acute Kidney Injury↗
PubMed1986

Simple method for monitoring 24-hour urinary urea nitrogen excretion.

The urine urea nitrogen/urine creatinine excretion ratio (UUN/UCr) of a "spot" urine specimen obtained approximately 5 hours after the last meal of the day can be used to accurately calculate the urinary urea excretion for the previous 24-hour period. Because UUN excretion is largely determined by dietary intake of protein nitrogen, this method can be used to estimate dietary protein intake for the previous 24-hour period. Strategies for using this simple method for inexpensively and continuously monitoring dietary protein intake are discussed.

Creatinine↗
PubMed1985

Atheroembolic renal disease causes hypocomplementaemia.

7 patients with atheroembolic renal disease were found to have hypocomplementaemia. Evidence obtained in an experimental model of atheroembolic disease shows that the hypocomplementaemia is the result of complement activation by the atheromatous material in vivo. In addition to hypocomplementaemia, 6 patients had thrombocytopenia and 5 had eosinophilia. These observations indicate that atheroembolic disease should now be included in the differential diagnosis of hypocomplementaemia. In addition, atheroembolic disease should be considered in patients presenting with a combination of multisystem disease, hypocomplementaemia, thrombocytopenia, and eosinophilia--a syndrome which previously would have been regarded as diagnostic of immune-complex-mediated vasculitis.

Aged↗
PubMed1985

Responses of the normal rat kidney to sequential ischemic events.

UNLABELLED: This study was undertaken to help define how one episode of renal ischemia, insufficient to cause acute renal failure, influences the susceptibility of the kidney to a second more severe ischemic event. Female Sprague-Dawley rats underwent either 15 min of bilateral renal artery occlusion (RAO) or sham RAO. They were subjected 30 min, 3.5 h, or 24 h later to 25 min of RAO. Renal function (GFR, BUN, creatinine), histology, and adenine nucleotide concentrations were compared before and after the 25-min ischemic event. Only the rats with a 30-min hiatus between the 15- and 25-min bouts of RAO had significantly worse renal failure than controls subjected to a single 25-min ischemic event. Three findings were noted only in the rats with increased susceptibility: tubular cell swelling and luminal membrane injury prior to 25 min of RAO and a relative failure of ATP formation immediately following 25 min of RAO. Susceptibility to 25 min of RAO did not correlate with preischemia ATP content. CONCLUSION: prior mild ischemic injury transiently lowers renal resistance to a second ischemic event. Normal resistance is rapidly restored once improvements in prior cell membrane injury, cell volume regulation, and cellular energetics occur. However, resistance to additional ischemia can be normal despite persisting depressions in renal ATP content.

Acute Kidney Injury↗
PubMed1985

Effects of mannitol on the postischemic kidney. Biochemical, functional, and morphologic assessments.

UNLABELLED: To determine the effects of mannitol on the postischemic kidney rats were subjected to 25 minutes of renal artery occlusion and immediately after vascular clamp release they received a 2-ml intravenous mannitol bolus (20%). Equimolar urea-injected rats and sham-injected rats served as controls. Postischemic renal blood flow, tubular metabolic work (renal O2 consumption), adenine nucleotide pools, renal oxidant stress (tissue glutathione, malondialdehyde levels), and tubular cell/mitochondrial swelling (histomorphometry) were assessed at variable times during the early vascular reflow period (15 to 60 minutes). The severity of acute renal failure was determined by serial blood urea nitrogen and serum creatinine studies (24, 48 hours), and by renal histology (48 hours). Mannitol increased postischemic renal blood flow (2-fold), renal O2 consumptions (3-fold), and urine flow compared to urea-injected and sham-injected controls. Postischemic glutathione levels were equally depressed (reduced 33%) in all three treatment groups. Malondialdehyde did not rise. Mannitol significantly lowered total adenine nucleotide content without changing ATP at 15 minutes post renal artery occlusion. At 60 minutes post renal artery occlusion, mannitol- and urea-treated groups had comparable ATP levels, 25% higher than the noninjected controls. Mannitol and urea induced comparable decrements in proximal tubular cell swelling, returning cell volumes to normal values. However, mitochondrial swelling was unabated. Mannitol and urea caused significant and nearly identical degrees of functional and morphologic amelioration of renal injury. CONCLUSIONS: Mannitol administered after renal ischemia ameliorates both functional and morphologic aspects of acute tubular injury despite dramatically increasing tubular aerobic work. This protection appears not to be due to early postischemic improvements in adenine nucleotide content, to increased renal blood flow, to increased urine flow, or to a lessening of oxidant stress. The data are consistent with the view that protection results from acute hypertonic solute loading which either directly or indirectly decreases tubular cell but not mitochondrial swelling.

Acute Kidney Injury↗
PubMed1985

Effects of immediate blood flow enhancement on the postischemic kidney: functional, morphologic, and biochemical assessments.

Our purpose was to assess the influence of blood flow enhancement to the immediate postischemic kidney on tubular cell energetics and on the severity of the resulting ischemic acute renal failure (IARF). Female Sprague-Dawley rats were subjected to 40 minutes of bilateral renal artery occlusion (RAO). Half of the rats received a 5% body weight infusion of iso-oncotic saline solution (IOS; over 50 minutes) to acutely increase renal blood flow (RBF) immediately after vascular clamp release. The remaining half of the rats served as controls. The short-term effects (0 to 1 hour after vascular reflow) of IOS infusion on RBF, clearance iothalamate sodium (Cioth), urine Na excretion (UNaE), urine flow rate, tubular metabolic work (renal oxygen consumption, Qo2), adenine nucleotide concentrations, and renal histologic findings were assessed. The severity of the IARF (Cioth histologic findings) was also compared between the IOS-treated and the control groups 24 hours later. Postischemic (0 to 1 hour) RBF in control IARF rats and IOS-treated IARF rats was 2.3 +/- 0.3 and 13.6 +/- 0.4 ml/min, respectively (P less than 0.01) (normal RBF 6.1 +/- 0.4 ml/min). At 0 to 1 hour after reflow IOS-treated IARF rats had significantly higher Cioth (13 X), UNaE (18 X), urine flow (18 X), and Qo2 (4 X) than the control IARF group. Despite the fourfold increase in aerobic tubular work induced by IOS infusion, renal adenosine triphosphate (ATP) content did not decrease. At 24 hours after vascular reflow the severity of IARF was the same in the control and IOS-treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1984

Responses of the ischemic acute renal failure kidney to additional ischemic events.

To test whether the ischemic acute renal failure (IARF) kidney has increased susceptibility to additional ischemic events, IARF was induced in female Sprague-Dawley rats [40 min of bilateral renal artery occlusion (RAO)] and either 18 or 48 hr later, at the height of morphologic injury, they were rechallenged with either 25 or 40 min of RAO. Changes in renal function (GFR, blood flow), morphology, and adenine nucleotide (AN) concentrations in response to these second ischemic challenges were compared to those of normal kidneys subjected to a single ischemic event. In additional experiments, rates of recovery from IARF were compared between rats subjected to one or two bouts of RAO (40 min, 24 hr apart). IARF kidneys retained a significantly greater percent of their baseline GFR and had comparable or higher absolute GFRs after 25 or 40 min of RAO than control rats. IARF rats showed no significant exacerbation of their underlying morphologic injury by superimposing a second ischemic event. IARF kidneys (24 hr post RAO) had normal AN concentrations, and by 30 min of reflow from a second 40 min of RAO, they re-established their AN energy charge and retained AN pools as well as control kidneys. A second 40-min bout of RAO did not significantly prolong recovery rates from the first 40-min ischemic event. In additional experiments, intraperitoneal injection of normal urine or solute matched artificial urine (urea, creatinine, NaCl) into normal rats to mimic the degree of azotemia seen in the IARF rats induced significant and comparable protection against 40 min of RAO. We conclude that the IARF kidney, at or near the height of its functional and morphologic injury, does not have increased susceptibility to additional ischemic insults. Rather a modicum of protection appears to exist, possibly due to renal-failure-induced increments in solute loads per nephron.

Acute Kidney Injury↗
PubMed1984

Glomerulopathy does not increase renal susceptibility to acute ischemic injury.

To determine whether preexistent glomerular injury and the nephrotic syndrome increase renal susceptibility to ischemic renal injury, normal rats and rats with either experimental minimal-change disease (Adriamycin nephropathy) (AN) or membranous nephropathy (passive Heymann nephritis) (PHN) underwent renal functional and histologic studies under either basal conditions or 18 h after bilateral renal artery occlusion (over 30 min). Prior to renal ischemia AN and PHN rats had minimally depressed glomerular filtration rate (GFR), normal (AN) or increased (PHN) renal blood flow (RBF), heavy proteinuria, hypoalbuminemia, decreased urine sodium excretion, extensive glomerular foot process fusion, and intratubular hyalin cast formation. Losses of GFR in response to ischemia were comparable among the three groups of rats (controls, 0.29; AN, 0.28; PHN, 0.25 ml X min-1 X 100 g body wt-1) despite prevailing differences in postischemic hemodynamics. Neither light nor transmission electron microscopy showed any differences in the degree of ischemic renal injury. These results suggest that 1) glomerulopathy and the nephrotic syndrome do not significantly increase renal susceptibility to ischemic renal injury; 2) the syndrome of acute renal failure that occurs in patients with minimal-change glomerulopathy is not due to a marked susceptibility of these kidneys to clinically occult ischemic events; and 3) foot process fusion is probably not a pathophysiologically significant lesion in ischemic acute renal failure, as previously suggested.

Acute Disease↗
PubMed1984

Progressive renal insufficiency induces increasing protection against ischemic acute renal failure.

The purpose of this study was to determine whether progressive renal insufficiency alters the resistance of residual nephrons to ischemic acute renal failure. Normal rats were subjected to either sham nephrectomy (2K rats; n = 7); right nephrectomy (1K rats; n = 7); or right nephrectomy plus variable degrees of ablation (one third to three fourths) of the left kidney (less than 1K rats; n = 10). Nine additional 1K rats received varying doses of nephrotoxic antiserum (NTX rats). One week later, glomerular filtration rate was determined and then ischemic acute renal failure was induced in all remaining renal tissues (25-minute renal artery occlusion). After ischemia, glomerular filtration rate was measured for 160 minutes, renal blood flow was determined, and the kidneys were fixed by in vivo perfusion. The 2K and non-NTX 1K rats had comparable percent recoveries of glomerular filtration rate (22% +/- 5%; 23% +/- 5%) despite a 64% higher renal blood flow for the 1K group. The less than 1K rats had a significantly higher percent recovery of glomerular filtration rate (53% +/- 11%; p less than 0.01), their absolute postischemic glomerular filtration rates were comparable to those of the 2K rats, and they showed significantly less morphologic evidence of ischemic renal injury (p less than 0.01). Both NTX and non-NTX rats with renal ablation showed a strong inverse correlation between baseline glomerular filtration rate and log percent filtration rate recovery (r = -0.75, p less than 0.02; r = -0.83, p less than 0.001, respectively). The less than 1K rats (n = 6) subjected to ischemia 1 day (rather than 1 week) after renal ablation were not protected against acute renal failure (18 +/- 5%) filtration rate recovery) despite renal blood flow comparable with that in other less than 1K rats. In conclusion, progressive renal insufficiency can confer increasing protection on residual nephrons against ischemic acute renal failure once a threshold reduction in functioning renal mass is achieved (greater than 1K). The present data suggest that this protection is not a result of compensatory renal hypertrophy, increased blood flow, or increased solute excretion per nephron, but probably arises as a delayed consequence of renal insufficiency-induced alterations of the internal milieu.

Acute Kidney Injury↗
PubMed1983

Fatty acid metabolism and cell proliferation: IV. Effect of prostanoid biosynthesis from endogenous fatty acid release with cyclosporin-A.

Cyclosporin-A (Cyc-A) stimulates prostanoid (PGI2) synthesis in confluent smooth muscle cells from guinea pig aorta through the release of endogenous fatty acid. Cyc-A, like other stimulatory agents for prostanoids, promotes smooth muscle cell proliferation and prostanoid synthesis in these proliferating cells. Indomethacin, a cyclooxygenase inhibitor, and exogenous arachidonic acid block the Cyc-A effect on cell proliferation.

Animals↗
PubMed1983

Potentiation of ischemic renal injury by amino acid infusion.

The purpose of this study was to determine whether amino acid hyperalimentation sensitizes the kidney to ischemic renal injury. Sprague-Dawley rats were infused with a control infusate or control infusate plus 15 essential and nonessential amino acids (FreAmine III, 2 mg of amino acids/kg/min). After 1 hr, bilateral renal ischemia was induced (15 min pedicle cross clamp). GFR, urine flow, and renal blood flow (RBF) were measured before and for 0 to 2 hr postischemia. None of these parameters were statistically different between the two groups of rats prior to renal ischemia. However, the decrease in GFR following renal ischemia was twice as great in the amino acid versus the nonamino acid treatment group (decreases 73 +/- 4% vs. decreases 36 +/- 4%, respectively; P less than 0.001). The postischemia urine flow rate was also significantly less (P less than 0.01) with amino acid treatment. RBF did not differ between the two groups. Renal histology confirmed greater tubular injury with amino acid treatment (P less than 0.001). In conclusion, infusion of therapeutic doses of amino acids can exacerbate early functional and histologic parameters of ischemic renal injury and thus, may sensitize the kidney to ischemic acute renal failure.

Acute Kidney Injury↗
PubMed1983

Organic anion infusions exacerbate experimental acute renal failure.

UNLABELLED: This investigation proposed to determine whether high organic anion (OA) loads per nephron increase renal susceptibility to acute ischemic and nephrotoxic injury. Anesthetized Sprague-Dawley rats were infused with a control infusate, Na2SO4, or an OA (hippurate, p-aminohippurate, cephalothin; 0.125-1.0 mg/min). After a 40-min control period, acute renal injury was induced by either bilateral renal pedicle cross-clamping (X25 min) or by HgCl2 administration (12 mg/kg i.v.). Glomerular filtration rate (clearance of [125I]iothalamate) was determined every 20 min before and after renal injury. Non-OA-infused rats lost 51 +/- 4% (ischemia) and 40 +/- 4% (HgCl2) of control GFR. OA infusion exacerbated this loss of renal function (ischemia, 89 +/- 2%; HgCl2, 84 +/- 4%). Renal histology demonstrated that OA-treated acute renal failure (ARF) rats had more vacuolar degeneration of proximal tubular cells (HgCl2, ischemia) and greater tubular dilatation (ischemia) than did non-OA-treated ARF rats. These functional and histologic responses to OA infusion were not OA dose dependent. Discontinuation of OA infusion did not cause a subsequent rise in GFR. Na2SO4 infusion had no detrimental effects on ischemic ARF. Control rats subjected to prolonged OA infusion (1 mg/min X 5 h) maintained stable GFR and had normal renal histology. ARF rats infused with low-dose cephalothin had terminal serum cephalothin concentrations within a range commonly seen in humans. CONCLUSION: organic anion infusions can exacerbate early functional and histologic parameters of experimental ARF.

Acute Kidney Injury↗