Reduction in cold ischemia time of renal allografts in the United States over the last decade.

A reduction in cold ischemia time (CIT) can be associated with better renal allograft outcomes. However, few published surveys of CIT of deceased donor kidneys transplanted in the United States are available. We therefore surveyed the CIT using the United Network for Organ Sharing data of the last decade. A reduction in CIT was observed during the 10-year period with an overall reduction of 4.8 hour (n = 75,072; mean +/- SD, 24.4 +/- 10.9 hour in 1990 vs 19.6 +/- 8.4 hour in 2000, P < .001) with fewer kidneys being cold-stored over 30 hour in the second half (13% in 1996 to 2000 vs 25% in 1990 to 1995, P < .001). Although the overall rates of delayed graft function were not different between the two periods (24% in 1990 to 1995 vs 25% in 1996 to 2000), possibly due to increased use of kidneys from extended criteria donors and donors after cardiac death and the persistence of CIT over 20 hours in the second half, the 6-month posttransplant graft function (serum creatinine: 1.63 +/- 0.01 mg/dL in 1996 to 2000 vs 1.75 +/- 0.01 mg/dL in 1990 to 1995; P < .001) and the 3-year graft survival (80% in 1996 to 2000 vs 72% in 1990 to 1995; P < .001) were better. Thus, our analysis demonstrates an overall reduction in mean CIT over the last decade, with fewer kidneys being cold-stored over 30 hours in the latter half. This raises the possibility that besides the influence of improved immunosuppression, reduction in CIT might have also contributed to the recently observed improvements in graft outcomes.

Overexpression of heme oxygenase protects renal tubular cells against cold storage injury: studies using hemin induction and HO-1 gene transfer.

Heme oxygenase-1 (HO-1), a 32-kd microsomal enzyme, is induced as an adaptive response to a wide variety of injurious stimuli. We examined the possible role of HO-1 in cold storage of renal proximal tubular epithelial (RPTE) cells. Hemin, a potent HO-1-inducer, caused a time-dependent increase in HO-1 mRNA and protein expression. Hemin pretreatment of human RPTE cells before cold storage conferred cytoprotection. Increased HO-1 protein was associated with a brisk and early increase in catalytically active iron and a robust increase in cellular ferritin. Deferoxamine, an iron sequestrating antioxidant, prevented hemin-induced iron release and the increase in ferritin, suggesting iron release as an antecedent mechanism for ferritin induction. To verify that the proximate cause of hemin cytoprotection was due to HO-1 induction, we transiently transfected LL-CPK1 porcine kidney cells with a HO-1 expression vector before cold storage. HO-1 transfection resulted in increased expression of HO-1 protein and reduced cell injury during cold storage. The novel observation that prior induction of HO-1 prevents cold storage-induced cell injury suggests that a similar strategy may prove efficacious in preventing cold storage-induced organ damage during transplantation.

Are conventional cardiovascular risk factors predictive of two-year mortality in hemodialysis patients?

BACKGROUND: In general population hypertension, diabetes mellitus, overweight, hyperlipidemia and smoking are well-established risk factors for cardiovascular disease. However, the effect of these conventional risk factors on cardiovascular disease and mortality of patients on hemodialysis is not well understood. Indeed, some risk factors such as high blood pressure, hyperlipidemia and excess weight have been recently claimed to correlate with improved survival. OBJECTIVE: This study was undertaken to define the prevalence of these conventional risk factors in 453 hemodialysis patients, predominantly African-Americans, to determine their influence on two-year survival. RESULT: High cholesterol was found in 30% of the patients, high LDL-cholesterol in 25% and high triglycerides in 16%. Lipoprotein(a) (LP(a)) was elevated in 68% of the patients. 31% of our patients had predialysis mean arterial blood pressure (MAP) over 114, and 25% were obese based on a body mass index (BMI) over 30, 26% were diabetic and 25% were active smokers. Smoking was more common among our male and Caucasian patients. The aggregate score for the risk factors were 2.4+/-0.1 per patient, which increased to 3.2+/-0.1 in patients with obesity or diabetes, to 3.0+/-0.1 with hypertension and to 2.8+/-0.1 with active smoking. In multivariate Cox model analysis, prealbumin, body weight and blood pressure showed a positive correlation with two-year survival whereas diabetes mellitus had a negative correlation. Hyperlipidemia did not correlate to patients' two-year mortality. Smoking was associated with higher mortality, but that did not reach statistical significance. CONCLUSION: Conventional risk factors at least over a two-year period do not readily account for the higher mortality of a group of predominantly African-American patients on hemodialysis. The lack of prediction is speculated to be partly due to the overriding beneficial effects of better nutrition and due to the presence of other yet to be well-defined factors such as hyperhomocysteinemia, oxidative stress, coronary calcification, hitherto unidentified uremic toxins or a combination of these factors.

Apoptosis versus necrosis during cold storage and rewarming of human renal proximal tubular cells.

BACKGROUND: A recent clinical study demonstrated that in renal allografts preserved in the cold apoptosis occurred soon after reperfusion. The mode of cell death during cold storage is generally considered necrotic. Whether apoptosis occurs as a part of cold storage is uncertain. The objective was to determine in human renal tubular cells whether apoptosis is specific for rewarming or it also occurs during cold storage and whether it could be modified. METHODS AND RESULTS: Cold storage (4 degrees C) of primary human renal proximal tubular epithelial (RPTE) in University of Wisconsin (UW) solution up to 48 hr caused a time-dependent increase in cell death measured by lactic dehydrogenase (LDH) release and vital dye exclusion methods. Transmission electron microscopy (TEM) demonstrated that cell death in the cold was necrotic, involving considerable mitochondrial disruption, and was not apoptotic. The TUNEL assay that provides a specific, quantitative measure for apoptosis showed no increase in TUNEL-positivity during flow cytometry of cells stored in cold: 37 degrees C, 0.23+/-0.14%; 24 hr cold, 0.23+/-0.1%; 48 hr cold, 1.79+/-0.58%. Annexin-V staining, a sensitive method for detecting early apoptosis, similarly showed no increase in positively stained cells during cold storage. Addition of antioxidants 2-methyl aminochroman and deferoxamine to UW solution inhibited necrotic cell death and preserved mitochondrial structure. In contrast to cold storage alone, rewarming (37 degrees C for 24 hr) of cold stored cells, however, resulted in significant apoptosis (TUNEL positive: 48 hr cold: 2+/-0.6%, 48 hr cold and 24 hr rewarming: 54+/-17%), which was confirmed by the TEM based on typical apoptotic features. Addition of 2-MAC and DFO significantly inhibited rewarming-induced apoptotic cell death (plus 2-MAC: 3+/-1%, plus DFO: 3+/-2%). CONCLUSION: Our study in human tubular cells provides evidence that cold storage per se does not result in apoptosis, but is primarily necrotic. However, rewarming is associated with significant apoptosis in the presence of ongoing necrosis, speculatively due to the activation of the apoptotic enzymic process of sublethally injured cells. Inclusion of antioxidants in the storage solution confers protection against both cold storage and rewarming-induced necrosis and apoptosis.

Anemia and iron target realization in 1998: clinical management of anemia in 1,639 patients on hemodialysis.

Anemia management in hemodialysis patients continues to evolve, and recently, greater emphasis has been placed on the wider use of intravenous iron to maintain adequate iron levels. This survey provides scarcely available yet potentially useful information on the clinical treatment of anemia in a large cohort of hemodialysis patients. The erythropoietin and iron administration details and pertinent laboratory measurements from 1,639 patients were analyzed for the month of December, 1998. A standardized protocol had been used in that erythropoietin was begun at a total weekly dose of 150 U/kg IV or 100 U/kg subcutaneously and was then adjusted to maintain a hematocrit (Hct) of 33-36%. Iron supplements, oral, IV, or both, were administered to maintain percent transferrin saturation (TSAT) at 20-30% and/or a serum ferritin of 100-500 ng/ml. No intravenous iron was administered if the ferritin was more than 500 ng/ml. Although 82% of patients were on iron supplementation and, among them, 58% were on IV iron, the percentage of patients with TSAT >20, i.e., bioavailable iron, was only 51%. The serum ferritin was high at 498 +/- 10 ng/ml (mean +/- SEM) and 88% and 10% of patients had serum ferritin >100 and >1,000 ng/ml, respectively, suggestive of sequestration of part of the infused iron. Erythropoietin was administered to 96% of patients, 99.5% by IV route. The latter was consistent with the US dialysis population at large but in variance with DOQI preference for the subcutaneous route. The target Hct range of 33-36 was found in 33%, with a mean Hct of 34.0 +/- 0.12. When the data were reanalyzed by excluding patients who had not been receiving erythropoietin and had not been on dialysis for at least 3 months, the percentage of patients achieving the target Hct increased to 37%. Paired analysis of 875 patients present in 1996 and 1998 showed that, although there was a marked increase in the use of IV iron, the improvement in anemia was modest, and there was evidence for increased iron accumulation. In summary, this 1998 survey on the clinical practice of anemia management in a large hemodialysis population indicates that there is a marked increase in need-based IV iron usage that was associated with modest improvement in anemia and evidence for increased iron storage. A maintenance iron dosing protocol with smaller doses of iron, such as 25 mg of iron dextran per hemodialysis, may make bioavailable iron continuously present for erythropoiesis, yet may reduce the chance for iron catalyzed lipid peroxidation and tissue iron deposition.

Increase in plasma esterified F2-isoprostanes following intravenous iron infusion in patients on hemodialysis.

BACKGROUND: In epoetin-treated dialysis patients, currently iron is administered by the intravenous route to maintain optimum erythropoiesis. However, rapid infusion of iron in excess of transferrin binding capacity can lead to the availability of unbound iron that can theoretically catalyze peroxidation of lipids, such as low-density lipoprotein (LDL), which when oxidatively modified is proinflammatory and promotes atherogenesis. METHODS: To address this issue, our study used one of the most specific measures of lipid peroxidation available, namely gas chromatography/mass spectometry (GC/MS) analysis of F2-isoprostanes. Using a prospective design, blood samples were collected 15 minutes before (pre) and 30 minutes after (post) a one-hour infusion of 700 mg bolus of intravenous iron in 22 adult home-hemodialysis patients on a non-hemodialysis day. RESULTS: With iron-dextran infusion, serum iron markedly increased (mean +/- SE, 42 +/- 4 vs. 311 +/- 92 microg/dL, P < 0.0001) and exceeded the transferrin saturation of 100% in 22 out of 22 patients (pre 23 +/- 3 vs. post 165 +/- 8%, P < 0.0001). Plasma concentrations of free F2-isoprostanes did not change significantly following infusion of iron (pre 40 +/- 5 vs. post 39 +/- 6 pg/mL). However, levels of F2-isoprostanes esterified in plasma lipoproteins increased significantly in the postinfusion samples (pre 199 +/- 19 vs. post 233 +/- 25 pg/mL, P < 0.004). Pre-infusion levels of serum iron correlated directly with pre-infusion levels of esterified F2-isoprostanes (r = 0.56, P = 0.008), which persisted in the postinfusion period (r = 0.43, P = 0.04). However, there was no correlation between esterified F2-isoprostanes and serum ferritin levels. In the last four patients in whom blood samples were collected five hours after the intravenous iron infusion, there were further increases in esterified F2-isoprostanes that very closely correlated with postinfusion serum iron levels (r = 0.99, P = 0.013). In a control study, the in vitro addition of iron dextran to blood samples did not increase free or esterified F2-isoprostanes, suggesting that the increase in esterified F2-isoprostanes seen in vivo after iron infusion in patients is not due to a procedural artifact. CONCLUSION: Collectively our data suggest that high levels of serum iron appearing soon after a large bolus of iron infusion is associated with significant, albeit modest, increases in levels of F2-isoprostanes esterified in plasma lipoproteins that tended to increase with time. Although it is uncertain whether this degree of lipid peroxidation may have deleterious effects, it may be sagacious to explore whether this can be prevented by slow infusion of frequent smaller doses of iron and, if necessary, along with administration of antioxidants.

Effect of 6 weeks of vitamin E administration on renal haemodynamic alterations following a single dose of neoral in healthy volunteers.

BACKGROUND: A single oral dose of cyclosporin-A (CsA) transiently reduces renal plasma flow (RPF) and glomerular filtration rate (GFR) in transplant patients and, in some patients, chronic administration of CsA leads to renal impairment and fibrosis. Based on experimental studies, several mediators including free radicals have been proposed to account for CsA-nephrotoxicity. We have previously reported that administration of the antioxidant vitamin E in a rat model of chronic CsA-nephrotoxicity reduces renal fibrosis and maintains renal function. METHODS: In the present study, the effect on renal haemodynamics of a single dose of the new oral formulation of CsA (neoral) was assessed before and after 6 weeks of vitamin E (800 IU/day, 2-fold increase in serum vitamin E). GFR (inulin clearance) and RPF (para-amino hippuric acid clearance) were measured before and after a single dose of 5 mg/kg of neoral in 12 healthy subjects under standardised conditions. RESULTS: Although the mean area under the curve of the CsA levels was 21% lower after the vitamin E period, the peak CsA level at 120 min after neoral was similar both before and after vitamin E administration. At 120 min after neoral, a transient reduction in RPF and GFR was noted both before and after vitamin E administration. The nadir of the reductions in RPF (-81 +/-27 ml/min) and GFR (-14 +/- 6 ml/min) at 120 min compared with baseline tended to be lower before than after the treatment with vitamin E (-51 +/- 33 ml/min of RPF and -12 +/- 8, ml/min of GFR, respectively). Plasma and urine levels of F2-isoprostanes (free radical-catalysed vasoconstrictive prostanoids (F2-iso) at 120 min after the administration of neoral were not different from the pre-neoral levels. CONCLUSION: The findings demonstrate that a single oral dose of neoral causes transient, yet significant, reductions in RPF and GFR, and suggest that F2-iso might not be involved in the CsA-induced acute renal vasoconstriction. The tendency for a lower reduction in RPF and GFR following CsA during the vitamin E period in healthy humans warrants additional studies in transplant patients.

Risk factor paradox in hemodialysis: better nutrition as a partial explanation.

The higher mortality rate in patients on hemodialysis is primarily due to the higher rate of cardiovascular disease. Yet, paradoxically, overweight, hypertension, and hyperlipidemia, which are cardiovascular risk factors in the general population, have been reported to correlate with better patient survival in hemodialysis. To examine whether this "risk factor paradox" in hemodialysis is due to the positive influence of accompanying better nutrition, we prospectively obtained data on fasting lipids, biochemical markers of nutrition, body mass index (BMI), and blood pressure (BP) in 453 hemodialysis patients and related them to 1 year mortality. As previously noted, body weight, blood pressure, and certain serum lipids positively correlated with survival. Serum prealbumin, one of the most sensitive and specific biochemical markers for nutrition, correlated positively with hypercholesterolemia (r = 0.30, p < 0.001) and BMI (r = 0.12, p < 0.02), but not with mean arterial pressure (MAP) (r = 0.01, p = NS). By analysis of variance, patients in the upper tertile (i.e., higher levels) of BMI and cholesterol but not MAP had significantly higher serum prealbumin and creatinine compared with those in the lower tertile. Our data lend support to the hypothesis that, in patients on hemodialysis, the positive effect of higher BMI and hyperlipidemia but not of high BP could be partially explained on the basis of the accompanying better nutrition. Although not proven, correcting risk factors while improving nutrition may offer better outcomes for patients on dialysis.

Lazaroid compounds prevent early but not late stages of oxidant-induced cell injury: potential explanation for the lack of efficacy of lazaroids in clinical trials.

Earlier in vitro studies demonstrated the remarkable potency of the lazaroid compounds to prevent oxidant-induced early cell injury. However, the ability of lazaroid compounds to limit oxidative injury in vivo(including renal ischemia-reperfusion) has been less certain, and the early clinical trials using lazaroids to limit CNS injury or organ injury in the setting of transplantation have not been promising. Lazaroid compounds are potent inhibitors of lipid peroxidation, and their inability to influence other key injury processes, particularly during the late stages of cell injury, might partly explain the limited clinical efficacy. To test this, renal tubular (LLC-PK1) cells were incubated with 250 micromH(2)O(2)for 135 min, in the presence or absence of 2-methyl aminochroman (2-MAC, U-83836E), a lazaroid with potent ability to inhibit lipid peroxidation, or desferrioxamine, (DFO) an iron chelator with broader antioxidant efficacy. Cell injury, lipid peroxidation, DNA damage and ATP depletion were measured in the early (immediately after H(2)O(2)incubation) and late (24 h after H(2)O(2)incubation) stages of cell injury. In the early stage, 2-MAC suppressed H(2)O(2)-induced lipid peroxidation and LDH release, but not the DNA damage, ATP depletion or loss of cell replication. In contrast, DFO suppressed all of the measurements. In the late stages, despite continued suppression of lipid peroxidation, only DFO maintained significant cytoprotection against H(2)O(2), and this was accompanied by reduced DNA damage, higher ATP levels and preservation of cell proliferation. Thus, the inability of the lazaroid compound 2-MAC to sustain cytoprotection in the later stages of cell injury might provide at least a partial explanation for the inefficiency of lazaroids to limit tissue injury in clinical and certain in vivo settings.

Vitamin E inhibits renal mRNA expression of COX II, HO I, TGFbeta, and osteopontin in the rat model of cyclosporine nephrotoxicity.

BACKGROUND: In a rat model of cyclosporine (CsA) nephrotoxicity, vitamin E preserves renal function and reduces free radicals, vasoconstrictive thromboxanes, and tubulointerstitial fibrosis. We examined the effect of vitamin E on tubule gene expression in this model. METHODS: In two of three groups, rats were treated with either CsA, or CsA plus vitamin E, whereas the control group received vehicles. We pooled purified tubules or whole kidney tissue in a novel manner to represent each treatment group, harvested RNA, and performed rigorously controlled qualitative reverse transcription-polymerase chain reaction. RESULTS: Cyclooxygenase (COX) I mRNA was detectable in control animals, was increased by CsA, but was unchanged by vitamin E. COX II mRNA was detected in controls, was inhibited in the CsA group, and was further inhibited with vitamin E. Hemeoxygenase I and TGF-beta and osteopontin mRNA were increased in the CsA-treated group and were inhibited by vitamin E. CONCLUSIONS: Our data support the involvement of free radicals, COX pathways, and pro-fibrotic genes in cyclosporine nephrotoxicity and suggest that the salutary effect of vitamin E involves the suppression of some of these genes.

Mechanism and prevention of cold storage-induced human renal tubular cell injury.

BACKGROUND: The recent observation that cold storage of kidneys and tubular cells causes marked increase in free radical-catalyzed F2-isoprostanes suggests that radicals might be formed during cold storage. As cold temperature is associated with reduced metabolic and enzymic activity, the notion that cold temperature causes free radical production appeared less tenable. The objective was, therefore, to seek direct evidence for the free radical production during the cold storage of human renal tubular cells, and to define the roles of extrinsic and intrinsic antioxidants in cold-induced cell injury. METHODS: Human renal tubular cells were cold-stored at 4 degrees C for varying duration in University of Wisconsin solution and subjected to mRNA analysis, biochemical measurements, and cytoprotective studies. RESULTS: Cold storage caused a time-dependent reduction in glutathione levels, and an increase in the formation superoxide, hydrogen peroxide, and hydroxyl radicals. Cold-induced lactate dehydrogenase (LDH) release, ATP depletion, DNA damage, and membrane degradation were suppressed with the inclusion of antioxidant 2-methyl aminochroman or deferroxamine. The cells that were structurally protected with antioxidants were also intact functionally, as they had significantly improved cell proliferation. To examine the effect of cold on intrinsic antioxidant gene expression, antioxidant mRNA levels were analyzed using reverse transcription-polymerase chain reaction. The gene expression of mitochondrial Mn-superoxide dismutase (SOD), but not of cytosolic Cu,Zn-SOD or of glutathione peroxidase expression increased with cold exposure. The oxidant-sensitive gene heme oxygenase I increased slightly with 48-hr cold storage. CONCLUSIONS: Cold storage of human tubular cells causes marked increase in free radicals. These are likely of mitochondrial origin as there is a differential inducement of Mn-SOD gene, and are causal to cold-induced cell injury as extrinsic antioxidants abrogated the injury. Our findings support the strategy of adding antioxidants to preservation solutions or the strategy of pre-conditioning the organs to oxidative stress to minimize cold storage-induced organ damage.

Race-dependent survival disparity on hemodialysis: higher serum aluminum as an independent risk factor for higher mortality in whites.

The mortality rate on hemodialysis therapy remains unacceptably high, and it is worse in whites than blacks. Substantially elevated serum aluminum levels have been shown to predict mortality on hemodialysis. However, whether this is a factor in the race-dependent survival difference on hemodialysis therapy is presently unknown. To determine the relevance of serum aluminum level on race-dependent survival disparity on chronic hemodialysis therapy, 1-year survival of 118 whites was prospectively compared with 473 age- and sex-matched blacks. The variables predictive for survival, including serum aluminum level, were defined separately in whites and blacks using Cox univariate and multivariate analyses. The 1-year mortality rate was significantly greater in whites than blacks (18% versus 12%; P: < 0.001). Serum albumin level, body mass index (BMI), and creatinine level had a positive influence, whereas age had a negative influence on survival in both groups in the univariate analysis. The mean serum aluminum level was significantly greater in whites (n = 118) than blacks (n = 473; 20 +/- 2.3 versus 14 +/- 0.6 [SE] ng/mL; P: = 0.0009) and was not caused by increased duration on dialysis, increased prescription of aluminum-containing phosphate binders, or reduced delivered dose of dialysis. Unlike the blacks, serum aluminum levels had a significant negative influence on the survival of whites, and this persisted in multivariate analysis after controlling for age, sex, diabetes, albumin level, creatinine level, and BMI (relative risk, 1.013; 95% confidence interval, 1.004 to 1.023; P: < 0.007). In summary, this study suggests that whites undergoing hemodialysis may have greater serum aluminum levels than blacks, which might contribute to the whites' greater rate of mortality. Because hyperaluminemia is a modifiable risk factor, studies are required to verify our findings, explore the mechanism of elevated aluminum levels in whites, and test the hypothesis that reducing serum aluminum levels in whites may improve their survival.

Impact of lower delivered Kt/V on the survival of overweight patients on hemodialysis.

UNLABELLED: Impact of lower delivered Kt/V on the survival of overweight patients on hemodialysis. BACKGROUND: A recent study suggests that overweight (OW) patients on hemodialysis are more likely to receive inadequate doses of dialysis. Because underdialysis is associated with higher mortality, OW patients might be at risk for higher mortality. This is in contrast with our recent observation in which survival was better in OW patients on hemodialysis. The objective of this study was to verify whether being OW was associated with underdialysis and to determine the influence of underdialysis on the survival of OW patients. METHOD: Kt/V measurements were obtained in 1151 patients on hemodialysis for two consecutive months, and their survival was prospectively followed for nine months. Body weights were defined by body mass index (BMI): OW if BMI was> 27.5, underweight (UW) if BMI was <20, and normal weight (NW) if BMI was 20 to 27.5. RESULTS: The Kt/V was inversely related to BMI (r = -0. 30, P < 0.0001). Kt/V in the OW patients was significantly lower than Kt/V in the NW or UW patients. By using a Kt/V threshold of 1.2, more patients were underdialyzed in the OW group (24%) than in the NW (15%) or UW (7%) groups. Underdialysis in the whole study group was associated with a 1.6-fold increase in the relative risk (RR) for mortality. The risk was more pronounced (RR, 2.6) in the underdialyzed OW patients compared with adequately dialyzed OW patients. In multivariate analysis, underdialysis in OW patients (RR, 4.3), but not in UW or NW patients, was a significant and independent risk factor for mortality. CONCLUSION: Our results verify that in the current practice of dialysis prescription, OW patients are less likely to receive adequate dialysis, and, to our knowledge for the first time, suggest that such underdialysis in OW patients might exert a negative influence on their survival. Prospective studies are required to test whether ensuring adequate delivery of dialysis in the OW patients might further improve their survival.

Role of reactive oxygen metabolites in organophosphate-bidrin-induced renal tubular cytotoxicity.

Due to low toxicity to nontarget species and rapid degradation after its application, organophosphate (OP) remains a widely used class of pesticide. Suicidal or accidental overdose of OP can result in acute tubular necrosis. Experimental evidence shows little correlation between the renal tubular necrosis and the degree of OP-induced acetylcholinesterase inhibition, the main mechanism of OP's toxicity, suggesting the involvement of alternate mechanisms. Since reactive oxygen species (ROS) are known mediators of many toxin-induced renal injuries, this study was conducted to investigate whether ROS play a role in Bidrin (BD)-induced renal tubular epithelial cell (LLC-PK1) toxicity. BD is an OP insecticide formulation with dicrotophos as the active ingredient. LLC-PK1 cell death, determined by lactate dehydrogenase (LDH) release (% of total), rose concentration- and time-dependently after exposure of the cells to 1000, 1250, 1500, 1750, and 2000 ppm of BD for 6, 12, 24, and 48 h. Antioxidants 2-methylaminochroman (2-MAC; 0.3 to 2.5 microM) and desferrioxamine (DFO; 0.25 to 2 mM) reduced cell damage induced by 1250 ppm of BD over a 24-h incubation in a concentration-related manner. The greatest reductions in % LDH were produced by DFO 2 mM and 2-MAC 2.5 microM, both significantly lower than BD alone. H2O2 levels (micromol/mg protein per h) were significantly elevated after exposure to 1250 ppm of BD. Significantly increased malondialdehyde formation (nmol/mg protein) compared with control was also found in BD-exposed cells indicating enhanced lipid peroxidation. Malondialdehyde generation was significantly suppressed by 2-MAC and DFO. These results demonstrate that the organophosphate BD can cause direct tubular cytotoxicity, and implicate, at least in part, a role for ROS and accompanying lipid peroxidation in cytotoxicity. Based on these direct in vitro findings, it is hypothesized that, besides hypotension that often accompanies OP intoxication, OP-induced oxidative stress at the tubular level may play a role in the pathogenesis of acute tubular necrosis.

Massive intracerebral hemorrhage in an amphetamine addict.

A case of massive intracerebral hemorrhage, a rare but often fatal complication of amphetamine abuse, is described along with the review of the literature. There has been resurgence in the abuse of amphetamine. Amphetamine or other illicit drug abuse should be considered in young patients with cerebrovascular events.

Chronic aminoguanidine attenuates renal dysfunction and injury in aging rats.

We have previously shown that aging is associated with increased lipid peroxidation, reductions in renal function, and increased glomerular sclerosis. The mechanism(s) responsible for these age-related changes are not clear. The purpose of the present studies was to determine if there was an increase in inducible nitric oxide synthase (iNOS) with aging, and if so, whether inhibition of iNOS would prevent aging injury by preventing free radical-mediated lipid peroxidation. iNOS protein expression in the kidney increased by approximately 90% by 24 months. Inhibition of iNOS by aminoguanidine (0.1% in drinking water) for 9 months, beginning at 13 months of age, reduced blood pressure, improved glomerular filtration rate by 70%, and renal plasma flow by 40%, whereas glomerular sclerosis was considerably reduced. Renal F2-isoprostanes and malondialdehyde levels, markers of oxidative stress and lipid peroxidation, were not reduced by aminoguanidine. Aminoguanidine also did not attenuate immunostaining for advanced glycosylation end products (AGE) in the kidneys. These findings suggest that aminoguanidine attenuates aging renal dysfunction by inhibiting a pathophysiologic function of iNOS that is independent of free radical-mediated lipid peroxidation or significant effects on AGE deposition.

Influence of excess weight on mortality and hospital stay in 1346 hemodialysis patients.

BACKGROUND: Body mass index (BMI) at its extremes contributes to morbidity and mortality in the general population. Its influence on morbidity and mortality in patients on hemodialysis is not clearly defined. METHODS: The BMI in 1346 patients attending limited-care hemodialysis units across the state of Mississippi was determined, and its relation to one-year mortality and hospital stay was assessed using the Cox proportional hazard model. RESULTS: Of these patients, 89% were black, and 11% were white. Thirty-eight percent of patients were overweight (BMI > 27.5), and 13% were underweight (BMI < 20). The highest (27.60 +/- 0.29, mean +/- SE) and the lowest (24.54 +/- 0.48) BMI were noted in black females and white males, respectively. BMI, race, hematocrit (Hct), and biochemical markers of better nutrition positively influenced the survival, whereas age, serum globulin, and diabetes had a negative influence. In a Cox multivariate analysis, BMI, age, diabetes, prealbumin, and creatinine, but not race, serum albumin, Hct, or serum globulin, retained significant influence on survival. Compared with the normal weight (BMI between 20 and 27.5), the one-year survival rate was significantly higher in the overweight patients and lower in the underweight patients. With a one-unit increase in BMI over 27.5, the relative risk for dying was reduced by 30% (P < 0.04), and with a one-unit decrease in BMI below 20, the relative risk was increased by 1.6-fold (P < 0.01). Furthermore, underweight patients had significantly lower levels of biochemical markers of nutrition and higher frequency and longer duration of hospital stay. CONCLUSION: Adequate dialysis with special attention to proper nutrition aimed to achieve the high end of normal BMI may help to reduce the high mortality and morbidity in hemodialysis patients.