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C L Edelstein

Publications and source records attributed to C L Edelstein.

At least 37 records · Page 2Linked to original sources
PubMed1997

Emerging therapies for acute renal failure.

Ischemia is the most common cause of acute renal failure (ARF). In the last decade, several new and important pathophysiological mechanisms that underlie the renal dysfunction have been discovered. These pathophysiological mechanisms include the role of both calcium and calcium-dependent enzymes, oxidant stress, loss of polarity of the tubular cell, tubular obstruction and arginine-glycine-aspartic acid (RGD) peptides, neutrophils, intracellular adhesion molecules (ICAM), and growth factors. A better understanding of tubular and vascular mechanisms has led to therapeutic studies in animals and clinical trials in humans. In this review, the pathophysiology of ischemic ARF will be correlated with the rationale for both current and future therapies.

Acute Kidney Injury↗
PubMed1997

The nature of renal cell injury.

The main functional change in patients with acute renal failure (ARF) is a decrease in glomerular filtration rate (GFR). The virtual complete recovery of renal function in those patients who survive ARF, as well as the minimal renal histological abnormalities during ARF when the GFR is less than 10 ml/min, suggest that a major component of the renal tubular cell injury is sublethal or reversible. Experimental models of acute tubular necrosis frequently have placed the emphasis on irreversible proximal tubular cell death. The nature of the renal tubular cell injury in ischemic acute renal failure, however, includes not only cell death (necrosis or apoptosis) but also sublethal injury causing cell dysfunction. The role of intracellular calcium, the calcium-dependent enzymes calpain, phospholipase A2 and nitric oxide synthase (NOS), in the pathophophysiology of this renal tubular cell injury during hypoxia/ischemia is described. The effects of calpain and nitric oxide (NO) on the cytoskeleton and cell adhesion are discussed. Potential mechanisms whereby tubular injury leads to a profound fall in GFR, including increased tubuloglomerular feedback and increased distal tubular obstruction, in ischemic acute renal failure are proposed.

Acute Kidney Injury↗
PubMed1997

Effect of glycine on prelethal and postlethal increases in calpain activity in rat renal proximal tubules.

The effect of glycine on hypoxia- and ionomycin-induced increases in calpain activity in rat proximal tubules was determined. Calpain activity was determined both in vitro and in the intact cell using the fluorescent substrate N-succinyl-Leu-Leu-Val-Tyr-7-amido-4-methyl coumarin (N-succinyl-Leu-Leu-Val-Tyr-AMC) and Western blotting for calpain-specific spectrin breakdown products (BDP), respectively. At 7.5 minutes of hypoxia (prelethal injury model) there was a significant (10-fold) increase in in vitro calpain activity that was not inhibited by glycine. At 15 minutes of hypoxia (postlethal injury model) there was a further increase in calpain activity that was inhibited by glycine. Normoxic tubules incubated with the calcium ionophore ionomycin (5 microM) for two minutes and 10 minutes had a significant increase in calpain activity that was not inhibited by glycine. After 15 minutes of hypoxia in the presence of glycine, there was an increase in calpain-specific spectrin breakdown products (BDP) in both Triton X-100 soluble and cytosolic extracts from proximal tubules. Glycine in concentrations up to 10 mM had no direct effect on the in vitro calpain activity of purified calpains. The present study demonstrates that: (1) prelethal increases in calpain activity stimulated by hypoxia and ionomycin treatment are not affected by glycine; (2) calpain-mediated spectrin breakdown during hypoxia occurs in the presence of glycine; (3) glycine does prevent the additional postlethal increase in calpain activity probably by maintaining membrane integrity to calcium influx.

Animals↗
PubMed1996

Nitric oxide kinetics during hypoxia in proximal tubules: effects of acidosis and glycine.

In the present study, we directly monitored nitric oxide (NO) with an amperometric NO-sensor in suspensions of rat proximal tubules. Hypoxia-stimulated NO generation was characterized by an initial rise and a subsequent sustained increase which preceded cell membrane damage as assessed by lactic dehydrogenase (LDH) release. In contrast, the NO concentration remained unmeasurable in normoxic controls. Nitro-L-arginine-methyl ester (L-NAME) prevented the hypoxia-induced increase in NO in a dose dependent manner in parallel with incremental cytoprotection. The hypoxia-induced elevation in NO and the associated membrane injury were both markedly prevented by extracellular acidosis (pH 6.95). In vitro proximal tubular nitric oxide synthase (NOS) activity (3H-arginine to 3H-citrulline assay) was pH dependent with optimum activity at pH 8.0 and greatly reduced activity at acidic pH even in the presence of calcium and co-factors. However, glycine, a well recognized cytoprotective agent, did not attenuate the NO concentration during hypoxia. The present study therefore provides direct evidence that NO is generated by rat proximal tubules during hypoxia and demonstrates that the protective effect of low pH against hypoxic rat tubular injury is associated with an inhibition of this NO production.

Acidosis, Renal Tubular↗
PubMed1996

Modulation of hypoxia-induced calpain activity in rat renal proximal tubules.

The effect of the newly developed, nonpeptide, calpain inhibitor, PD 150606, on hypoxia and ionomycin-induced increases in calpain activity in rat proximal tubules (PT) was determined. PD150606 inhibited both hypoxia and ionomycin-induced calpain activity as determined by the fluorescent substrate N-succinyl-Leu-Leu-Val-Tyr-7-amido-4-methyl coumarin (N-succinyl-Leu-Leu-Val-Tyr-AMC). This decrease in calpain activity was accompanied by dose-dependent cytoprotection against hypoxia and ionomycin-induced cell membrane damage. PD150606 had no effect on cathepsin B and L activity in PT as measured by the fluorescent substrate, benzyloxycarbonyl-L-phenylalanyl-L-arginine-7-amido-4-methyl coumarin (Z-Phe-Arg-AMC). The effects of low intracellular pH (pHi) or low free cytosolic calcium [Ca2+]i on this hypoxia-induced calpain activity were also determined. Both low pHi and low [Ca2+]i attenuated the hypoxia-induced increase in calpain activity. This attenuation of calpain activity was observed early before hypoxia-induced membrane damage and was associated with marked reduction in the typical pattern of hypoxia-induced cell membrane damage observed in this model. To identify the isoform of calpain activated in rat proximal tubules, normoxic, hypoxic and ionomycin treated tubules were fractionated by MONO-Q anion exchange chromatography and the fractions were assayed for calpain activity. A single peak of calpain activity characteristic of mu-calpain was found. The calcium dependency of the calpain activity was in the nanomolar range, further confirming that the activity was the low Ca(2+)-sensitive mu-calpain. The present study suggests that in rat proximal tubules: (1) PD 150606 is a specific inhibitor of calpain and not cathepsins B and L; (2) the cytoprotective effects of low pHi and low [Ca2+]i are mediated, at least in part, by inhibition of calpain activity; and (3) the predominant active form of calpain is the isoenzyme mu-calpain.

Acrylates↗
PubMed1996

Arachidonic acid protects against hypoxic injury in rat proximal tubules.

Free fatty acids (FFA) and lysophospholipids accumulate during hypoxia (H) in rat proximal tubular epithelial cells partly as a result of increased phospholipase A2 (PLA2) activity. The role of FFA in mediating hypoxic injury and modulating PLA2 activity is not clear. In the present study, the effect of several FFA including arachidonic acid (AA, 20:4) on hypoxia-induced injury and PLA2 activity was assessed in freshly isolated rat proximal tubules. Hypoxia (H) was induced in the presence of either an unsaturated free fatty acid (uFFA) [AA or linoleic acid (LA, 18:2)] or a saturated FFA (sFFA) [palmitic (PA, 16:0) or myristic acid (MA, 14:0)]. Cell membrane injury was assessed by measuring lactate dehydrogenase release (LDH). AA markedly reduced LDH release during hypoxia in a dose dependent manner, while sFFA had no protective effect. LA showed similar protection to that observed with AA. AA did not affect buffer calcium concentration, buffer pH, intracellular pH or intracellular calcium concentration. Neither inhibiting the cyclooxygenase pathway with indomethacin, nor the lipoxygenase pathway with nordihydroguaiaretic acid (NDGA) had any effect on the AA observed cytoprotection. In vitro PLA2 activity in the control tubular extracts was compared to that following addition of AA or PA. PLA2 activity decreased significantly with AA but not with PA in a dose dependent manner. These data suggest that: (1) AA protects against hypoxic injury in rat proximal tubules. (2) This cytoprotection is not specific for AA and other uFFA have a similar effect. (3) AA significantly inhibits PLA2 activity, (4) AA induced cytoprotection may be related to a negative feedback inhibition of PLA2 activity.

Animals↗
PubMed1996

The role of the calcium-dependent enzymes nitric oxide synthase and calpain in hypoxia-induced proximal tubule injury.

A role of cytoplasmic free calcium [Ca2+]i in hypoxia-induced proximal tubule damage has been proposed. To further investigate the role of [Ca2+]i in mediating hypoxic proximal tubular injury, a video imaging technique has been developed in which [Ca2+]i can be measured simultaneously with propidium iodide (PI) staining of nuclei as an index of hypoxia-induced membrane damage. Hypoxia in rat proximal tubules is associated with a significant rise in [Ca2+]i which precedes evidence of membrane damage as assessed by PI staining. This rise in [Ca2+]i activates calpain, a Ca2+-dependent cysteine protease, and constitutive nitric oxide synthase (NOS), the Ca2+-dependent form of NOS. Inhibition of either calpain or nitric oxide synthase provides marked cytoprotection against hypoxic proximal tubular injury. These observations are consistent with the early rise in [Ca2+]i initiating hypoxic injury by activating NOS and calpain.

Acute Kidney Injury↗
PubMed1995

The role of cysteine proteases in hypoxia-induced rat renal proximal tubular injury.

The role of the lysosomal proteases cathepsins B and L and the calcium-dependent cytosolic protease calpain in hypoxia-induced renal proximal tubular injury was investigated. As compared to normoxic tubules, cathepsin B and L activity, evaluated by the specific fluorescent substrate benzyloxycarbonyl-L-phenylalanyl-L-arginine-7-amido-4-methylcoumarin, was not increased in hypoxic tubules or the medium used for incubation of hypoxic tubules in spite of high lactate dehydrogenase (LDH) release into the medium during hypoxia. These data in rat proximal tubules suggest that cathepsins are not released from lysosomes and do not gain access to the medium during hypoxia. An assay for calpain activity in isolated proximal tubules using the fluorescent substrate N-succinyl-Leu-Tyr-7-amido-4-methylcoumarin was developed. The calcium ionophore ionomycin induced a dose-dependent increase in calpain activity. This increase in calpain activity occurred prior to cell membrane damage as assessed by LDH release. Tubular calpain activity increased significantly by 7.5 min of hypoxia, before there was significant LDH release, and further increased during 20 min of hypoxia. The cysteine protease inhibitor N-benzyloxycarbonyl-Val-Phe methyl ester (CBZ) markedly decreased LDH release after 20 min of hypoxia and completely prevented the increase in calpain activity during hypoxia. The increase in calpain activity during hypoxia and the inhibitor studies with CBZ therefore supported a role for calpain as a mediator of hypoxia-induced proximal tubular injury.

Animals↗
PubMed1995

Hypoxia induces changes in phospholipase A2 in rat proximal tubules: evidence for multiple forms.

Increased free fatty release during hypoxia is believed to contribute to cell injury. This phenomenon is likely to be mediated through activation of specific isoforms of phospholipase A2 (PLA2). In this study, PLA2 enzymatic activity was measured in cell-free extracts prepared from rat renal proximal tubules. Both soluble and membrane-associated PLA2 activity were detected. All PLA2 activity detected during normoxia was Ca2+ dependent. Fractionation of cytosolic extracts by gel filtration revealed three peaks of PLA2 activity. Exposure of tubules to hypoxia resulted in stable activation of soluble PLA2 activity, which correlated with disappearance of the highest molecular mass form (> 100 kDa) and appearance of a low-molecular-mass form (approximately 15 kDa) of PLA2. Hypoxia also resulted in release of a low-molecular-mass form of PLA2 into the extracellular medium. Pretreatment of tubules with glycine before hypoxia blocked this release of PLA2 but not activation of soluble PLA2 activity. These studies provide direct evidence for PLA2 activation during hypoxia and suggest that multiple mechanisms regulate free fatty acid release associated with hypoxia injury.

Animals↗
PubMed1995

Pulmonary complications in 110 consecutive renal transplant recipients.

The pulmonary complications in 110 consecutive renal transplant recipients on cyclosporin and low-dose steroid immunosuppression were studied retrospectively. The pulmonary complications were: acute pulmonary oedema in 19 patients, pneumonia in 18, tuberculosis in 9, acute pulmonary embolism in 5, and lung abscess in 1. Sixty-nine patients (62.7%) had no pulmonary complications; 69% of the complications occurred in the first 4 months after the transplant. Pulmonary tuberculosis became evident later. The mean age, period of follow-up, human leucocyte antigen (HLA) B/DR mismatches, mean serum urea and serum creatinine concentrations, systolic and diastolic blood pressures, and cyclosporin dosage did not differ between the groups with no complications, infectious complications and non-infectious complications. The number of rejection episodes treated with bolus steroids was significantly higher in the infectious and non-infectious complications groups compared with the group with no complications. The incidence of pulmonary complications after renal transplantation, especially pneumonia and tuberculosis, was still high despite the use of low-dose steroids and cyclosporin. Pulmonary complications were the commonest cause of death in the first 3 years after the transplant. A high index of suspicion for pulmonary tuberculosis and pulmonary embolism in these patients is necessary.

Cyclosporine↗
PubMed1994

Treatment of methyl bromide poisoning with haemodialysis.

Acute accidental methyl bromide poisoning was treated with haemodialysis. The treatment was successful in removing bromide from the blood but the patient persists with severe neuropsychiatric sequelae. To the best of our knowledge haemodialysis has not been used previously for the treatment of organic bromide poisoning.

Acute Disease↗
PubMed1992

Systemic calciphylaxis presenting as a painful, proximal myopathy.

A renal transplant patient who presented with a painful, proximal myopathy due to systemic calciphylaxis is described. The myopathy preceded the characteristic skin and soft tissue necrosis. Systemic calciphylaxis should be considered in a dialysis or a renal transplant patient presenting with a painful proximal myopathy even in the absence of necrotic skin lesions.

Calciphylaxis↗
PubMed1992

Subtypes of acute postinfectious glomerulonephritis: a clinico-pathological correlation.

The case records and histopathology of 42 adults with the characteristic light and electron microscopic features of Acute Postinfectious Glomerulonephritis (APGN) were studied. The biopsies were divided into three subtypes depending on the form and distribution of subepithelial "humps" and other immune-complex deposits on electron microscopy (EM): the "starry sky", "garland" and "mesangial" patterns. There was no significant difference between the three subtypes with regard to age, hypertension, creatinine, anti-streptolysin 0 titer and low serum complement levels on presentation. The "garland" subtype had significantly more proteinuria than both the "starry sky" (p = 0.04) and "mesangial" (p = 0.003) subtypes. The "mesangial" pattern had a lesser degree of cellular proliferation and leukocytosis in the glomeruli than the other subtypes. The "starry sky" subtype was present in 4 of the 5 cases of crescentic nephritis and in 6 of the 7 patients with a chronic course. Our study suggests that the higher degree of proteinuria in the "garland" subtype and the chronic course of the "starry sky" subtype are the main clinical features that distinguish the three histological subtypes. Our patients, from a developing community with poor socio-economic conditions, had a poor prognosis.

Acute Disease↗