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Biomedical subjects

M Brezis

Publications and source records attributed to M Brezis.

At least 55 records · Page 3Linked to original sources
PubMed1995

The role of medullary ischemia in acute renal failure.

The introduction of new techniques for the determination of renal parenchymal oxygenation and intrarenal microcirculation has elucidated some important aspects in the pathophysiology of acute renal failure (ARF). Data accumulated over the last decade with these techniques, together with improved morphologic evaluation of the kidney, indicate that medullary damage may play a pivotal role in various forms of acute and chronic renal hypoxic and toxic insults. The outer medulla functions normally under hypoxic conditions, as a result of limited regional oxygen supply and high oxygen consumption for urinary concentration. Outer medullary oxygenation is critically balanced by mechanisms designed to adjust oxygen demand and supply, and their insufficiency may lead to ARF with hypoxic medullary damage. In this article, we outline our current concept of the physiologic control of medullary oxygenation and review the clinical conditions that predispose to hypoxic medullary damage, including rhabdomyolysis, hypercalcemia, or the exposure to endotoxin, nonsteroidal anti-inflammatory drugs, radiologic contrast agents, cyclosporine, FK506, and amphothericin. We shall indicate a possible role for medullary oxygen insufficiency in clinical conditions known to predispose to ARF, such as preexisting renal disease, diabetes mellitus, hypertension, atherosclerosis, effective volume depletion, urinary obstruction, or aging, and suggest potential strategies to preserve medullary oxygenation and integrity.

Acute Kidney Injury↗
PubMed1994

Determinants of intrarenal oxygenation. I. Effects of diuretics.

To study renal cortical and medullary oxygen tensions, we used sensitive Clark-type O2 microelectrodes, inserted by micromanipulators into the cortex and medulla of kidneys of anesthetized rats. As previously reported, under basal conditions, medullary PO2 was significantly lower than cortical PO2. Furosemide, which inhibits reabsorptive transport in the medullary thick ascending limb, increased medullary PO2 from 16 +/- 4 to 35 +/- 4 mmHg (P < 0.0005) without altering cortical PO2. This effect, reproduced by ethacrynic acid and bumetanide, was selective for loop diuretics and was directly due to decreased tubular O2 consumption, since medullary blood flow was remarkably reduced by furosemide (-28 +/- 6% from baseline, P < 0.0001, as measured by a laser-Doppler probe). By contrast, acetazolamide, which decreases proximal tubule metabolism, selectively increased cortical PO2. These data are, in general, consistent with tubular metabolism as a major determinant of intrarenal oxygenation and suggest, in particular, that medullary reabsorptive work is at least in part responsible for renal medullary hypoxia.

Absorption↗
PubMed1994

Determinants of intrarenal oxygenation. II. Hemodynamic effects.

To study hemodynamic effects on intrarenal oxygenation, O2 microelectrodes were inserted into rat kidneys. In a previous study [M. Brezis, Y. Agmon, and F. H. Epstein. Am. J. Physiol. 267 (Renal Fluid Electrolyte Physiol. 36): F1059-F1062, 1994], we showed that tubular metabolism is a major determinant of intrarenal oxygenation, in part responsible for medullary hypoxia observed under basal conditions. Acute hypotension (by controlled hemorrhage, aortic ligation, or nitroprusside infusion) paradoxically increased medullary PO2 (from 21 +/- 2 to 39 +/- 2 mmHg, P < 0.001) while decreasing cortical PO2 (from 46 +/- 2 to 32 +/- 3 mmHg, P < 0.001), abolishing corticomedullary gradients of oxygen. Laser-Doppler studies indicated that, while cortical blood flow was reduced during hypotension, medullary blood flow was unchanged or increased. The increase in medullary PO2 induced by hypotension was abolished by prior administration of furosemide, suggesting that during hypotension, reduced glomerular filtration rate (GFR), distal delivery, and reabsorption result in decreased oxygen utilization. Acute infusions of atriopeptin III (0.1-1 microgram.kg-1.min-1) decreased both cortical PO2 (from 61 +/- 2 to 55 +/- 2 mmHg, P < 0.001) and medullary PO2 (from 15 +/- 1 to 7 +/- 1 mmHg, P < 0.001), consistent with atriopeptin-induced increases in GFR and tubular reabsorptive work. These data suggest that medullary oxygen availability increases during renal hypoperfusion and may decrease during renal vasodilation.

Animals↗
PubMed1994

Nitric oxide and prostanoids protect the renal outer medulla from radiocontrast toxicity in the rat.

Human radiocontrast nephrotoxicity is predicted by the presence of multiple risk factors, often associated with compromised renal circulation. To produce a simple model of radiocontrast nephropathy, rats were pretreated with indomethacin and N omega-nitro-L-arginine methyl ester (L-NAME, to inhibit nitric oxide synthesis) before the administration of iothalamate. Acute renal failure consistently developed, with a decline in creatinine clearance from 1.05 +/- 0.10 to 0.27 +/- 0.05 ml/min (P < 0.001) associated with selective necrosis of 49 +/- 9% of medullary thick ascending limbs. Hemodynamic studies using laser-Doppler probes revealed that when injected alone, iothalamate increased outer medullary blood flow to 196 +/- 25% of baseline (P < 0.001). Pretreatment by L-NAME or indomethacin both reduced basal medullary blood flow and transformed the medullary vasodilator response to radiocontrast into vasoconstriction, with a prolonged reduction of medullary blood flow to less then half of baseline. Combined administration of indomethacin, L-NAME, and iothalamate lowered medullary blood flow to 12 +/- 4% of baseline. We conclude that prostanoids and nitric oxide have an important protective role in the renal response to radiocontrast material. Reduced synthesis of these vasoactive substances in renal/vascular diseases may predispose patients to radiocontrast nephropathy.

Acute Kidney Injury↗
PubMed1994

Effects of salt depletion on the kidney: changes in medullary oxygenation and thick ascending limb size.

Previous studies have shown that salt depletion enhances the susceptibility of the kidney to nephrotoxins (amphotericin, cyclosporine, and contrast). To study the renal response to salt depletion, Sprague-Dawley rats were fed a sodium-deficient diet (N = 12) with pair-fed controls (N = 13) for 4 wk. In addition, rats from each group underwent 24-h water deprivation studies (N = 9; four salt deprived, five normal). Plastic 1-micron horizontal sections of mid-inner stripe were examined, and cross-sectional areas of the medullary thick ascending limb (mTAL) were analyzed. The mTAL of the salt-deprived rats were smaller (P = 0.04) and showed greater variance in size (P = 0.02) than control (618 +/- 106 versus 693 +/- 50 microns2). However, mean glomerular and collecting duct cross-sectional areas were unaffected by salt intake. Cross-sectional areas of long- and short-loop mTAL were significantly different, regardless of group (518 +/- 78 versus 732 +/- 92 microns2). Maximal urinary concentrating ability was found to correlate with mTAL cross-sectional area (r = 0.85; P = 0.004) and with long-loop mTAL size (r = 0.77; P = 0.016). However, it did not significantly correlate with short loop mTAL size (r = 0.53; P = 0.14).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

The pathology of nephrotoxic injury: a reappraisal.

The class of nephrotoxins which are directly tubulotoxic in animal studies (cis-platinum, gentamicin, and cephaloridine) produce minimal histological changes in the human kidney. Such alterations do not correlate with the degree of organ dysfunction and fall into the broad category of what has been called 'acute tubular necrosis'. Some nephrotoxins (cyclosporine and amphotericin), acutely and chronically diminish renal perfusion, causing injury to renal parenchymal zones known to have limited oxygen a availability (medullary ray and inner stripe). In cyclosporine toxicity, the human and animal models appear equivalent. This is less clear with amphotericin where there appears to be a tubulotoxic component. Other nephrotoxic substances (contrast, nonsteroidal anti-inflammatory drugs) acutely alter renal perfusion, particularly affecting the medulla. In animal models of renal failure induced by these substances, there is an excellent correlation between medullary thick ascending limb injury and renal failure. Documentation of this phenomenon in human biopsies/autopsies is lacking, probably because of the lack of biopsy material and problems in defining medullary injury. Finally, in toxicological screening programs for nephrotoxic substances, there are groups of reactions which cannot be predicted and are thought to be mediated by immune mechanisms, i.e., immune complex glomerular disease, nil disease and interstitial nephritis.

Acute Kidney Injury↗
PubMed1993

Sodium loading and renal prostaglandins in old rats.

1. Previous studies have shown that altered synthesis of prostaglandins (PGs) in the kidney of ageing rats contributes to impaired Na conservation during sodium deprivation. In the present study, we wished to assess whether the disturbance of prostaglandin synthesis also affects the response to sodium loading in old rats. 2. We measured the urinary excretion of thromboxane B2 (TXB2), 6-keto PGF1 alpha (6KPGF1 alpha) and PGE2 in young (3-4 months) and old (20-21 months) rats after 24, 48 and 72 h of Na loading. In a separate protocol, we measured prostanoid synthesis by isolated glomeruli, cortical homogenates, medullary and papillary slices from young and old rats in basal conditions and after 15 days of dietary Na loading. 3. Young and old rats excreted similarly the Na load. The urinary excretion (U) of TXB2 and 6KPGF1 alpha were unchanged during Na load in young rats. U6KPGF1 alpha, which was significantly higher in old rats and UTXB2 which also tended to be elevated, decreased in old rats with Na loading. Sodium loading was associated with a transient increase of UPGE2 in young, but not in old rats. 4. TXB2 synthesis was increased in all portions of the kidneys of old rats. 6KPGF1 alpha production was elevated in glomeruli and cortex and that of PGE2 in cortex. In medulla and papilla only TXB2 synthesis was enhanced. 5. Sodium loading did not significantly change prostanoid synthesis in the kidneys of young rats. In old rats, glomerular and cortical TXB2 decreased whereas medullary and papillary 6KPGF1 alpha increased.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1993

Effects of ioversol versus iothalamate on endothelin release and radiocontrast nephropathy.

RATIONALE AND OBJECTIVES: Certain radiocontrast agents, including iothalamate, iohexol, and ioxaglate, release the renal vasoconstrictor peptide endothelin from vascular endothelium in a way that might contribute to radiocontrast nephropathy. The effects of the nonionic, low osmolar agent, ioversol, on endothelin release and renal function are investigated. METHODS: Effects of ioversol were compared with equi-iodine doses of iothalamate when applied to cultured bovine aortic endothelial cells or injected into normal rats and rats preconditioned by uninephrectomy, salt depletion, and indomethacin (USIC) to develop radiocontrast nephropathy. RESULTS: In comparison with iothalamate, ioversol had a greatly reduced propensity to stimulate the release of endothelin, from cultured cells and when injected into anesthetized rats. Ioversol produced less renal vasoconstriction than did iothalamate, in control and in USIC rats, and the development of radiocontrast nephropathy, assessed by creatinine clearance and morphologic damage to the renal medulla, was largely avoided. CONCLUSIONS: These results strengthen the hypothesis that endothelin release induced by radiocontrast agents is correlated with their renal toxicity and therefore, may play a role in radiocontrast nephropathy.

Animals↗
PubMed1993

Cellular mechanisms of acute ischemic injury in the kidney.

Hypoxic injury to tubular cells represents an early event in acute renal failure. Although important advances have been made in the understanding of hypoxic injury at the cellular level (e.g. loss of cell polarity, production of free radicals, calcium entry, and the activation of genes for protection or regeneration), the basic mechanisms responsible for organ failure remain elusive. The renal medulla, working on the brink of anoxia and being the site of concentration for many toxins, may be an important target for the synergistic events of hypoperfusion and nephrotoxic exposure that often precede human acute renal failure.

Acute Kidney Injury↗
PubMed1993

Disparate effects of adenosine A1- and A2-receptor agonists on intrarenal blood flow.

Endogenous adenosine, secreted locally by the kidney during tissue hypoxia, induces heterogeneous renal hemodynamic responses. We investigated the cortical and outer medullary blood flow responses to intrarenal infusions of adenosine and adenosine A1- and A2-receptor agonists in anesthetized rats. These agents were infused into the renal interstitium through chronically implanted capsules, and blood flow was measured by laser-Doppler probes. Short (1 min, 0.05 ml) intrarenal infusions of adenosine (0.5 mumol) lowered cortical blood flow to 27 +/- 10% of baseline (n = 7, P < 0.0005). Medullary blood flow response was biphasic, i.e., a transient decrease in flow to 52 +/- 8% of baseline (n = 17, P < 0.0001) followed by a more-sustained increase in flow to 135 +/- 6% (n = 17, P < 0.0001). N6-cyclopentyladenosine, an adenosine receptor A1 agonist, reduced both cortical and medullary blood flow to 59 +/- 4% (n = 10, P < 0.0001) and 38 +/- 5% (n = 11, P < 0.0001) of baseline, respectively. By contrast, 2-[p- (carboxyethyl)phenethylamino]-5'-N-ethycarboxamidoadenosine (CGS-21680C), an adenosine receptor A2 agonist, increased dramatically the medullary blood flow to 184 +/- 15% of baseline (n = 12, P < 0.0005), without major changes in cortical flow. We conclude that intrarenal adenosine reduces cortical blood flow and predominantly increases medullary flow via A1 and A2 receptors, respectively. These hemodynamic responses could play a role in protection of the outer medulla from hypoxia.

Adenosine↗
PubMed1993

Chronic amphotericin nephropathy: morphometric, electron microscopic, and functional studies.

The two major hypotheses for the pathogenesis of amphotericin nephrotoxicity are direct interaction with epithelial cell membranes and vasoconstriction. Studies indicating the special vulnerability of the medullary ray and medulla to hypoxia led to a reexamination of amphotericin nephrotoxicity. Twenty-four rats were divided into four groups: amphotericin injection (5 mg/kg daily for 3 wk), amphotericin plus salt depletion, vehicle, and salt depletion and vehicle. The amphotericin group had polyuria (P < 0.01) but normal serum creatinine. In contrast, amphotericin plus salt depletion rats exhibited renal failure (creatinine of 1.49 +/- 0.05 versus amphotericin alone 0.98 +/- 0.01; P < 0.01). Semiquantitative histologic analysis of cortical and medullary injury correlated with functional impairment. Cortical changes in the amphotericin group were largely restricted to the medullary ray, where focal rupture and calcification of thick ascending limbs were noted. The S2/S3 tubules in the medullary rays showed focally diminished cell complexity with histiocytic/lymphocytic infiltration. However, calcification was also seen in the area of the macula densa. Morphometry revealed that the thick ascending limbs in the medulla were hypertrophied (1,420 +/- 63 versus 1,195 +/- 48 microns 2 for vehicle; P < 0.05). In contrast, in the amphotericin and salt depletion group, the changes in the medullary ray extended to the labyrinth and the thick ascending limbs in the inner stripe showed atrophic changes (772 +/- 23 microns 2; P < 0.01 versus vehicle). Thus, changes as a result of amphotericin toxicity take place both in areas known to be most vulnerable to hypoxia (medullary ray and medulla), and in areas rich in oxygen (adjacent to glomerulus). Salt depletion potentiates the cortical changes and converts medullary hypertrophy to atrophy. These findings support a dual pathogenesis for amphotericin nephropathy (direct toxicity and vasoconstriction).

Amphotericin B↗