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Biomedical subjects

C L Edelstein

Publications and source records attributed to C L Edelstein.

At least 19 recordsLinked to original sources
PubMed2006

Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery.

Acute kidney injury (AKI) is a frequent complication of cardiopulmonary bypass (CPB). The lack of early biomarkers for AKI has impaired our ability to intervene in a timely manner. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is recently demonstrated as an early biomarker of AKI after CPB, increasing 25-fold within 2 h and declining 6 h after surgery. In the present study, we tested whether interleukin-18 (IL-18) is a predictive biomarker for AKI in the same group of patients following CPB. Exclusion criteria included pre-existing renal insufficiency and nephrotoxin use. Serial urine samples were analyzed by enzyme-linked immunosorbent assay for IL-18 in 20 patients who developed AKI (defined as a 50% or greater increase in serum creatinine after CPB) and 35 controls (age, race, and gender-matched patients who did not develop AKI after CPB). Using serum creatinine, AKI was detected only 48-72 h after CPB. In contrast, urine IL-18 increased at 4-6 h after CPB, peaked at over 25-fold at 12 h, and remained markedly elevated up to 48 h after CPB. The performance of IL-18 as demonstrated by area under the receiver operating characteristics curve for diagnosis of AKI at 4, 12, and 24 h after CPB was 61, 75, and 73% respectively. Also, on multivariate analysis, both IL-18 and NGAL were independently associated with number of days in AKI among cases. Our results indicate that IL-18 is an early, predictive biomarker of AKI after CPB, and that NGAL and IL-18 are increased in tandem after CPB. The combination of these two biomarkers may allow for the reliable early diagnosis and prognosis of AKI at all times after CPB, much before the rise in serum creatinine.

Acute Kidney Injury↗
PubMed2006

Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation.

Delayed graft function (DGF) due to tubule cell injury frequently complicates deceased donor kidney transplants. We tested whether urinary neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL-18) represent early biomarkers for DGF (defined as dialysis requirement within the first week after transplantation). Urine samples collected on day 0 from recipients of living donor kidneys (n = 23), deceased donor kidneys with prompt graft function (n = 20) and deceased donor kidneys with DGF (n = 10) were analyzed in a double blind fashion by ELISA for NGAL and IL-18. In patients with DGF, peak postoperative serum creatinine requiring dialysis typically occurred 2-4 days after transplant. Urine NGAL and IL-18 values were significantly different in the three groups on day 0, with maximally elevated levels noted in the DGF group (p < 0.0001). The receiver-operating characteristic curve for prediction of DGF based on urine NGAL or IL-18 at day 0 showed an area under the curve of 0.9 for both biomarkers. By multivariate analysis, both urine NGAL and IL-18 on day 0 predicted the trend in serum creatinine in the posttransplant period after adjusting for effects of age, gender, race, urine output and cold ischemia time (p < 0.01). Our results indicate that urine NGAL and IL-18 represent early, predictive biomarkers of DGF.

Acute-Phase Proteins↗
PubMed2005

Caspases as drug targets in ischemic organ injury.

Caspases are intracellular cysteine proteases that mediate cell death and inflammation. Caspase-3 is a major mediator of both apoptotic and necrotic cell death. Caspase-1 mediates inflammation though the activation of the cytokines interleukin-1beta (IL-1beta) and interleukin-18 (IL-18). Increases in both caspase-1 and -3 have been described in ischemic injury to various organs including brain, heart and kidney. Both pharmacological inhibitors and genetic approaches have been used to inhibit caspases in vivo. Pancaspase inhibitors protect against ischemic injury in brain, heart and kidney. Pancaspase inhibition also reduces cold preservation injury due to apoptosis in liver endothelial cells and prolongs animal survival after orthotopic liver transplantation. Caspase-1 inhibition or caspase-1 deficiency protects against ischemic injury in brain, heart and kidney models of ischemia. Specifically, impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. This review focuses on studies of caspase-1 and pancaspase inhibition in ischemic injury to brain, heart and kidney. In addition, the studies of pancaspase inhibition in cold ischemic injury and organ preservation will be reviewed. The therapeutic potential of caspase inhibition in ischemic injury will be discussed.

Animals↗
PubMed2001

Endotoxemic renal failure in mice: Role of tumor necrosis factor independent of inducible nitric oxide synthase.

BACKGROUND: Renal failure is a frequent complication of sepsis with a high mortality. Tumor necrosis factor (TNF) has been suggested to be a factor in the acute renal failure in sepsis or endotoxemia. Recent studies also suggest involvement of nitric oxide (NO), generated by inducible NO synthase (iNOS), in the pathogenesis of endotoxin-induced renal failure. The present study tested the hypothesis that the role of TNF in endotoxic renal failure is mediated by iNOS-derived NO. METHODS: Renal function was evaluated in endotoxemic [Escherichia coli lipopolysaccharide (LPS), 5 mg/kg IP] wild-type and iNOS knockout mice. The effect of TNF neutralization on renal function during endotoxemia in mice was assessed by a TNF-soluble receptor (TNFsRp55). RESULTS: An injection of LPS to wild-type mice resulted in a 70% decrease in glomerular filtration rate (GFR) and in a 40% reduction in renal plasma flow (RPF) 16 hours after the injection. The results occurred independent of hypotension, morphological changes, apoptosis, and leukocyte accumulation. In mice pretreated with TNFsRp55, only a 30% decrease in GFR without a significant change in RPF in response to LPS, as compared with vehicle-treated mice, was observed. Also, the serum NO concentration was significantly lower in endotoxemic wild-type mice pretreated with TNFsRp55, as compared with untreated endotoxemic wild-type mice (260 +/- 52 vs. 673 +/- 112 micromol/L, P < 0.01). In LPS-injected iNOS knockout mice and wild-type mice treated with a selective iNOS inhibitor, 1400W, the development of renal failure was similar to that in wild-type mice. As in wild-type mice, TNFsRp55 significantly attenuated the decrease in GFR (a 33% decline, as compared with 75% without TNFsRp55) without a significant change in RPF in iNOS knockout mice given LPS. CONCLUSIONS: These results demonstrate a role of TNF in the early renal dysfunction (16 h) in a septic mouse model independent of iNOS, hypotension, apoptosis, leukocyte accumulation, and morphological alterations, thus suggesting renal hypoperfusion secondary to an imbalance between, as yet to be defined, renal vasoconstrictors and vasodilators.

Acute Kidney Injury↗
PubMed2001

Role of polymeric Tamm-Horsfall protein in cast formation: oligosaccharide and tubular fluid ions.

BACKGROUND: In acute tubular necrosis (ATN), distal tubules are obstructed by casts formed by tubular debris, cells, and Tamm-Horsfall protein (THP). Since there are Arginine-Glycine-Aspartate (RGD) and Leucine-Aspartate-Valine (LDV) adhesive sequences in human THP, there may be direct integrin-mediated binding of tubular cells to THP. Alternatively, polymerization of THP may result in entrapment of the cells in its gel. METHODS: Adhesion of LLC-PK(1) cells to THP-coated wells was directly measured. THP concentrate was dissolved in solutions which mimic urine from ATN (ATN-S), distal convoluted tubule (DCT-S), collecting duct (CD-S), and monomeric buffer (M buffer). THP was also denatured by either boiling or N-glycanase digestion. Gel formation of THP was then measured. Inhibition of LLC-PK(1) cell adhesion to collagen type I was measured with each solution, as well as after the collagen was pretreated with either monomeric (mTHP) or polymeric (pTHP) THP. The effect of pTHP on the settling rate of LLC-PK(1) cells in suspension was also measured. RESULTS: LLC-PK(1) cells did not directly adhere to THP, a finding against integrin-mediated binding as a mechanism for in vivo tubular cell/THP cast formation. The high electrolyte concentration of ATN-S and CD-S, however, was associated with pTHP gel formation. Moreover, cells suspended in pTHP remained in suspension. In cell adhesion studies, mTHP attenuated cell adhesion by binding to the matrix, whereas pTHP attenuated cell adhesion by trapping cells in its gel. An active process was involved since both pTHP gel formation and attenuation of cell adhesion were abolished by boiling or oligosaccharide removal with N-glycanase digestion. CONCLUSIONS: With renal ischemia and proximal tubule cell shedding, ATN and collecting duct fluid composition enhance THP gel formation and thus favor tubular cast formation and obstruction. The present in vitro results indicate the importance of oligosaccharide residues in mediating the effect of the THP on gel formation and potential cast formation in ATN.

Animals↗
PubMed2001

Calpain inhibition protects against virus-induced apoptotic myocardial injury.

Viral myocarditis is an important cause of human morbidity and mortality for which reliable and effective therapy is lacking. Using reovirus strain 8B infection of neonatal mice, a well-characterized experimental model of direct virus-induced myocarditis, we now demonstrate that myocardial injury results from apoptosis. Proteases play a critical role as effectors of apoptosis. The activity of the cysteine protease calpain increases in reovirus-infected myocardiocytes and can be inhibited by the dipeptide alpha-ketoamide calpain inhibitor Z-Leu-aminobutyric acid-CONH(CH(2))3-morpholine (CX295). Treatment of reovirus-infected neonatal mice with CX295 protects them against reovirus myocarditis as documented by (i) a dramatic reduction in histopathologic evidence of myocardial injury, (ii) complete inhibition of apoptotic myocardial cell death as identified by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling, (iii) a reduction in serum creatine phosphokinase, and (iv) improved weight gain. These findings are the first evidence for the importance of a calpain-associated pathway of apoptotic cell death in viral disease. Inhibition of apoptotic signaling pathways may be an effective strategy for the treatment of viral disease in general and viral myocarditis in particular.

Animals↗
PubMed2001

Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure.

We sought to determine whether mice deficient in the proinflammatory caspase-1, which cleaves precursors of IL-1 beta and IL-18, were protected against ischemic acute renal failure (ARF). Caspase-1(-/-) mice developed less ischemic ARF as judged by renal function and renal histology. These animals had significantly reduced blood urea nitrogen and serum creatinine levels and a lower morphological tubular necrosis score than did wild-type mice with ischemic ARF. Since caspase-1 activates IL-18, lack of mature IL-18 might protect these caspase-1(-/-) mice from ARF. In wild-type animals, we found that ARF causes kidney IL-18 levels to more than double and induces the conversion of the IL-18 precursor to the mature form. This conversion is not observed in caspase-1(-/-) ARF mice or sham-operated controls. We then injected wild-type mice with IL-18-neutralizing antiserum before the ischemic insult and found a similar degree of protection from ARF as seen in caspase-1(-/-) mice. In addition, we observed a fivefold increase in myeloperoxidase activity in control mice with ARF, but no such increase in caspase-1(-/-) or IL-18 antiserum-treated mice. Finally, we confirmed histologically that caspase-1(-/-) mice show decreased neutrophil infiltration, indicating that the deleterious role of IL-18 in ischemic ARF may be due to increased neutrophil infiltration.

Acute Kidney Injury↗
PubMed2000

Effect of antihypertensive therapy on renal function and urinary albumin excretion in hypertensive patients with autosomal dominant polycystic kidney disease.

Hypertensive patients with autosomal dominant polycystic kidney disease (ADPKD) have a faster progression to end-stage renal disease (ESRD) than their normotensive counterparts. The aim of this prospective, randomized study is to compare the effects of the calcium channel blocker amlodipine and the angiotensin-converting enzyme inhibitor enalapril as first-line therapy on blood pressure, renal function, and urinary albumin excretion in hypertensive patients with ADPKD. Twenty-four patients with ADPKD with hypertension with creatinine clearances (Ccrs) greater than 50 mL/min/1.73 m(2) were included in the study. Twelve patients received amlodipine (mean dose, 9 mg/d), and 12 patients received enalapril (mean dose, 17 mg/d). The patients were followed up for 5 years. Baseline mean arterial pressures, which were 109 +/- 3 mm Hg in the amlodipine group and 108 +/- 3 mm Hg in the enalapril group, decreased significantly after 1 year of follow-up (amlodipine, 96 +/- 3 mm Hg; P < 0.005; enalapril, 89 +/- 2 mm Hg; P < 0.0005) and remained stable at year 5 (amlodipine, 97 +/- 3 mm Hg; P < 0.0005 versus baseline; enalapril, 94 +/- 3 mm Hg; P < 0.005 versus baseline). Ccrs, which were 83 +/- 5 mL/min/1.73 m(2) in the amlodipine group and 77 +/- 6 mL/min/1.73 m(2) in the enalapril group, remained stable after 1 year of follow-up and decreased significantly at year 3 in both groups (amlodipine, 67 +/- 5 mL/min/1.73 m(2); P < 0.01 versus year 1 and baseline; enalapril, 58 +/- 4 mL/min/1.73 m(2); P < 0.05 versus year 1 and P < 0.0005 versus baseline) with no significant change thereafter. No change was observed in urinary albumin-creatinine ratio in the amlodipine group (baseline, 68 +/- 21 mg/g; year 1, 52 +/- 21 mg/g; year 5, 148 +/- 74 mg/g), whereas it decreased significantly in the enalapril group at year 1 (baseline, 23 +/- 4 mg/g; year 1, 13 +/- 3 mg/g; P < 0.05) and remained stable until the end of the study at year 5 (14 +/- 6 mg/g). The investigators concluded that blood pressure was similar in both groups but only enalapril had a significant effect to sustain decreased urinary albumin excretion for a 5-year follow-up. Although proteinuria has been considered a surrogate of renal disease progression, further studies will be necessary to confirm this hypothesis in ADPKD, because after 5 years, no differences in renal function were observed between the enalapril and amlodipine groups. In comparison with patients with ADPKD with uncontrolled hypertension, effective control of blood pressure, as undertaken in the present study, should delay the onset of ESRD by approximately 15 years.

Adult↗
PubMed2000

Progress in blood pressure control in autosomal dominant polycystic kidney disease.

Hypertension occurs commonly in autosomal dominant polycystic kidney disease (ADPKD) and is an important factor in the progression of the disease and cardiovascular mortality. The aim of this prospective 15-year study is to report the rate of blood pressure control and the potential effect of a 10-point education program developed by our center for ADPKD patients and their physicians. The patients' blood pressure treatment was managed by their primary care physicians. Three 5-year periods were analyzed in which similar rates of hypertension in patients with ADPKD were present (63% to 68%). In the first period (1985 to 1989), the rate of blood pressure control (<140/90 mm Hg) was 38% for 216 hypertensive patients with ADPKD. From 1990 to 1994, the percentage of blood pressure control increased to 55% in 194 hypertensive patients with ADPKD (P < 0.001 versus 1985 to 1989); and the level of blood pressure control increased to 64% in 181 hypertensive patients with ADPKD during 1995 to 1999 (P < 0.001 versus 1985 to 1989). Although this percentage of blood pressure control in patients with ADPKD remains suboptimal, it compares very favorably with the 27% estimated blood pressure control in patients with essential hypertension from 1991 to 1994 in the United States.

Adult↗
PubMed2000

Downregulation of the calpain inhibitor protein calpastatin by caspases during renal ischemia-reperfusion.

The interaction between the cysteine proteases calpain and caspases during renal ischemia-reperfusion (I/R) was investigated. An increase in the activity of calpain, as determined by 1) the appearance of calpain-mediated spectrin breakdown products and 2) the conversion of procalpain to active calpain, was demonstrated. Because intracellular calpain activity is regulated by calpastatin, the effect of I/R on calpastatin was determined. On immunoblot of renal cortex, there was a 50-100% decrease of a low molecular weight (LMW) form of calpastatin (41 kDa) after I/R. Calpastatin activity was also significantly decreased after I/R compared with sham-operated rats, indicating that the decreased protein expression had functional significance. In rats treated with the caspase inhibitor, z-Asp-2,6-dichlorobenzoyloxymethylketone (Z-D-DCB), the decrease in both calpastatin activity and protein expression was normalized, suggesting that caspases may be proteolyzing calpastatin. Caspase 3 activity increased significantly after I/R and was attenuated in ischemic kidneys from rats treated with the caspase inhibitor. In summary, during renal I/R injury, there is 1) calpain activation associated with downregulation of calpastatin protein and decreased calpastatin activity and 2) activation of caspase 3. In addition, in vivo caspase inhibition reverses the decrease in calpastatin activity. In conclusion, proteolysis of calpastatin by caspase 3 may regulate calpain activity during I/R injury. Although the protective effect of cysteine protease inhibition against hypoxic necrosis of proximal tubules has previously been demonstrated, the functional significance in ischemic acute renal failure in vivo merits further study.

Animals↗
PubMed1999

Effect of nitric oxide donors on renal tubular epithelial cell-matrix adhesion.

BACKGROUND: Nitric oxide (NO) and its metabolite, peroxynitrite (ONOO-), are involved in renal tubular cell injury. We postulated that if NO/ONOO- has an effect to reduce cell adhesion to the basement membrane, this may contribute to tubular obstruction and may be partially responsible for the harmful effect of NO on the tubular epithelium during acute renal failure (ARF). METHODS: We examined the effect of the NO donors (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1- ium-1, 2-diolate (DETA/NO), spermine NONOate (SpNO), and the ONOO- donor 3-morpholinosydnonimine (SIN-1) on cell-matrix adhesion to collagen types I and IV and fibronectin using three renal tubular epithelial cell lines: LLC-PK1, BSC-1, and OK. RESULTS: In LLC-PK1 cells, DETA/NO (500 microM) had no effect, and SpNO (500 microM) had a modest effect on cell adhesion compared with controls. Exposure to SIN-1 caused a dose-dependent impairment in cell-matrix adhesion. Similar results were obtained in the different cell types and matrix proteins. The effect of SIN-1 (500 microM) on LLC-PK1 cell adhesion was not associated with either cell death or alteration of matrix protein and was attenuated by either the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, the superoxide scavenger superoxide dismutase, or the ONOO- scavenger uric acid in a dose-dependent manner. CONCLUSIONS: These results therefore support the possibility that ONOO- generated in the tubular epithelium during ischemia/reperfusion has the potential to impair the adhesion properties of tubular cells, which then may contribute to the tubular obstruction in ARF.

Animals↗
PubMed1999

Reversal of left ventricular hypertrophy with angiotensin converting enzyme inhibition in hypertensive patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Hypertension occurs commonly and early in the natural history of autosomal dominant polycystic kidney disease (ADPKD), affecting both renal and patient outcome. Activation of the renin angiotensin aldosterone system due to cyst expansion and local renal ischaemia plays an important role in the development of ADPKD related hypertension and left ventricular hypertrophy (LVH), a known important risk factor for cardiovascular morbidity and mortality. The aim of this study was to investigate the effects of an angiotensin converting enzyme (ACE) inhibitor, enalapril, on renal function, blood pressure and LVH in hypertensive ADPKD patients. METHODS: Fourteen hypertensive ADPKD patients (11 men, 3 women; mean age: 40 years) were included in the study. All patients had LVH and creatinine clearance (Cer) greater than 50 ml/min/1.73 m2. The patients were followed for 7 years on enalapril therapy. The effects of enalapril on renal function, blood pressure and LVH were investigated. RESULTS: Baseline measurements of mean arterial pressure (MAP), Ccr and left ventricular mass index (LVMI) were 110 +/- 2 mmHg, 84 +/- 6 ml/min/1.73 m2 and 146 +/- 4 g/m2, respectively. After one year of enalapril therapy there was a significant decrease in MAP (94 +/- 3 mmHg, P < 0.005) which remained stable until the end of the study at 7 years (94 +/- 1 mmHg, P < 0.005 vs baseline). There was also a significant decrease in LVMI (131 +/- 6 g/m2, P < 0.05) after year 1 which continued to decrease until the end of the study reaching 98 +/- 6 g/m2 (P < 0.01 vs year 1 and baseline). Although Ccr remained stable after year 1, a significant decrease was observed after 7 years of follow-up (59 +/- 6 ml/min, P < 0.001 vs year 1 and baseline). CONCLUSIONS: ACE inhibition in hypertensive ADPKD patients provided long-term reversal of LVH in association with a mean 3.6 ml/min/year decline of Ccr. These preliminary results have potential important implications for cardiovascular and renal protection in ADPKD.

Adult↗
PubMed1999

Role of caspases in hypoxia-induced necrosis of rat renal proximal tubules.

The role of the caspases, a newly discovered group of cysteine proteases, was investigated in a model of hypoxia-induced necrotic injury of rat renal proximal tubules. An assay for caspases in freshly isolated rat proximal tubules was developed. There was a 40% increase in tubular caspase activity after 15 min of hypoxia in association with increased cell membrane damage as indicated by a threefold increase in lactate dehydrogenase release. The specific caspase inhibitor Z-Asp-2,6-dichlorobenzoyloxymethylketone (Z-D-DCB) attenuated the increase in caspase activity during 15 min of hypoxia and markedly decreased lactate dehydrogenase release in a dose-dependent manner. In the proximal tubules, Z-D-DCB also inhibited the hypoxia-induced increase in calpain activity, another cysteine protease. In contrast, when Z-D-DCB was added to purified calpain in vitro, there was no inhibition of calpain activity. The calpain inhibitor (2)-3-(4-iodophenyl)-2-mercapto-2-propenoic acid (PD150606) also inhibited the hypoxia-induced increase in caspase activity in proximal tubules, but did not inhibit the activity of purified caspase 1 in vitro. In these experiments, caspase activity was detected with the fluorescence substrate Ac-Tyr-Val-Ala-Asp-7-amido-4-methyl coumarin (Ac-YVAD-AMC), which is preferentially cleaved by caspase 1. However, minimal caspase activity was detected with the fluorescence substrate Ac-Asp-Glu-Val-Asp-7-amido-4-methyl coumarin (Ac-DEVD-AMC), which is cleaved by caspases 2, 3, and 7. The present study in proximal tubules demonstrates that (1) caspase inhibition protects against necrotic injury by inhibition of hypoxia-induced caspase activity; and (2) caspase 1 may be the caspase involved. Thus, although the role of caspases in apoptotic cell death is well established, this study provides new evidence that caspases contribute to necrotic cell death as well.

Animals↗
PubMed1998

Effect of hypoxia on proximal tubules isolated from nitric oxide synthase knockout mice.

Nitric oxide (NO) has been shown to be a mediator of hypoxic injury in rat renal proximal tubules (PT). However, the role of NO in hypoxic injury to mouse. PT has not been examined. The aim of the present study was to determine the effect of knockout of nitric oxide synthase (NOS) isoforms on hypoxic injury in mouse PT. Mouse PTs were isolated by collagenase digestion and Percoll centrifugation. The nonselective NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME, 10 mM), but not its inactive stereoisomer D-NAME, protected against hypoxic injury as assessed by LDH release. Carboxy-imidazolineoxyl N-oxide (carboxy-PTIO, 100 microM), a stable NO scavenger, also afforded cytoprotection against hypoxic injury. To determine the role of the different NOS isoforms in the hypoxic injury, we examined the effect of hypoxia on PT isolated from knockout mice in which either the inducible NOS (iNOS) endothelial NOS (eNOS) or neuronal NOS (nNOS) gene was lacking. PT isolated from iNOS knockout mice were resistant to hypoxic injury compared to wild-type controls. In contrast, PT isolated from both nNOS and eNOS knockout mice were not protected against hypoxic injury. In conclusion, the present study demonstrates that NO is a mediator of hypoxic PT injury in the mouse and that knockout of the iNOS gene is cytoprotective against this hypoxic PT injury.

Animals↗