Biased reporting of past self-injurious thoughts and behaviors: A literature review.

BACKGROUND: Accurate assessment of suicide risk is critical for clinical practice, empirical advances, and informing public policy. In this narrative review of the literature, we compiled evidence from longitudinal studies that identify reporting bias of past self-injurious thoughts and behaviors (SITB) and examined possible correlates of inconsistent reporting. METHOD: We conducted an extensive literature search, including 19 longitudinal samples or subsamples who reported the presence of current or past SITB at an initial but not at a subsequent assessment (yes/no inconsistent reports). RESULTS: The median was 33%, and the weighted mean was 39% (95% CI, 37%-41%) for the prevalence of inconsistent reporting of SITB across the longitudinal samples. Importantly, inconsistent reports were linked with less internalizing psychopathology and more adaptive functioning. The type of sample recruited and assessment interval may also be relevant factors to consider. LIMITATIONS: Variability of sample characteristics and methodology made it challenging to draw firm conclusions across studies but provide information about critical sources of bias. CONCLUSIONS: Results suggest considerable caution for clinical, empirical, and policy decision-making based on lifetime reports of suicide and encourage a continued consideration for identifying potential reporting biases for SITB.

Basal and reactive cortisol: A systematic literature review of offspring of parents with depressive and bipolar disorders.

One of the most consistent biological findings in the study of affective disorders is that those with depression commonly show abnormal cortisol response, which suggests dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Children of parents with mood disorders offer the opportunity to explore the biological pathways that may confer risk for psychopathology. This review explores basal and reactive cortisol in the offspring of parents who are currently depressed or have had a history of a depressive or bipolar disorder. Using PRISMA guidelines, search terms yielded 2002 manuscripts. After screening, 87 of these manuscripts were included. Results from the literature suggest that while the degree and direction of dysregulation varies, offspring of a parent with depression tend to show elevations in both basal (particularly morning and evening) and reactive (tentatively for social stressors) cortisol levels. There were few studies focused on offspring of parents with bipolar disorder. This review also discusses implications and recommendations for future research regarding the HPA axis in the intergenerational transmission of depressive disorders.

Multimodal assessment of sustained threat in adolescents with nonsuicidal self-injury.

Nonsuicidal self-injury (NSSI) is a common but poorly understood phenomenon in adolescents. This study examined the Sustained Threat domain in female adolescents with a continuum of NSSI severity (N = 142). Across NSSI lifetime frequency and NSSI severity groups (No + Mild NSSI, Moderate NSSI, Severe NSSI), we examined physiological, self-reported and observed stress during the Trier Social Stress Test; amygdala volume; amygdala responses to threat stimuli; and resting-state functional connectivity (RSFC) between amygdala and medial prefrontal cortex (mPFC). Severe NSSI showed a blunted pattern of cortisol response, despite elevated reported and observed stress during TSST. Severe NSSI showed lower amygdala-mPFC RSFC; follow-up analyses suggested that this was more pronounced in those with a history of suicide attempt for both moderate and severe NSSI. Moderate NSSI showed elevated right amygdala activation to threat; multiple regressions showed that, when considered together with low amygdala-mPFC RSFC, higher right but lower left amygdala activation predicted NSSI severity. Patterns of interrelationships among Sustained Threat measures varied substantially across NSSI severity groups, and further by suicide attempt history. Study limitations include the cross-sectional design, missing data, and sampling biases. Our findings highlight the value of multilevel approaches in understanding the complexity of neurobiological mechanisms in adolescent NSSI.

Symptomatic BK Virus Infection Is Associated With Kidney Function Decline and Poor Overall Survival in Allogeneic Hematopoietic Stem Cell Recipients.

Nephropathy due to BK virus (BKV) infection is an evolving challenge in patients undergoing hematopoietic stem cell transplantation (HSCT). We hypothesized that BKV infection was a marker of kidney function decline and a poor prognostic factor in HSCT recipients who experience this complication. In this retrospective study, we analyzed all patients who underwent their first allogeneic HSCT at our institution between 2004 and 2012. We evaluated the incidence of persistent kidney function decline, which was defined as a confirmed reduction in estimated glomerular filtration rate of at least 25% from baseline using the Chronic Kidney Disease Epidemiology equation. Cox proportional hazard regression was used to model the cause-specific hazard of kidney function decline, and the Fine-Gray method was used to account for the competing risks of death. Among 2477 recipients of a first allogeneic HSCT, BK viruria was detected in 25% (n = 629) and kidney function decline in 944 (38.1%). On multivariate analysis, after adjusting for age, sex, acute graft-versus-host disease (GVHD), chronic GVHD, preparative conditioning regimen, and graft source, BK viruria remained a significant risk factor for kidney function decline (p < 0.001). In addition, patients with BKV infection and kidney function decline experienced worse overall survival. After allogeneic HSCT, BKV infection was strongly and independently associated with subsequent kidney function decline and worse patient survival after HSCT.

A facile thermal-treatment route to synthesize ZnO nanosheets and effect of calcination temperature.

A facile thermal-treatment route was successfully used to synthesize ZnO nanosheets. Morphological, structural, and optical properties of obtained nanoparticles at different calcination temperatures were studied using various techniques. The FTIR, XRD, EDX, SEM and TEM images confirmed the formation of ZnO nanosheets through calcination in the temperature between 500 to 650 °C. The SEM images showed a morphological structure of ZnO nanosheets, which inclined to crumble at higher calcination temperatures. The XRD and FTIR spectra revealed that the samples were amorphous at 30 °C but transformed into a crystalline structure during calcination process. The average particle size and degree of crystallinity increased with increasing calcination temperature. The estimated average particle sizes from TEM images were about 23 and 38 nm for the lowest and highest calcination temperature i.e. 500 and 650 °C, respectively. The optical properties were determined by UV-Vis reflection spectrophotometer and showed a decrease in the band gap with increasing calcination temperature.

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.

Possible involvement of oxidative stress in cisplatin-induced apoptosis in LLC-PK1 cells.

Use of cisplatin, a chemotherapeutic agent, is associated with toxicity as a significant number of patients develop a decline in renal function. The mechanisms by which cisplatin produces renal injury are not well understood. It has been suggested that free radical-catalyzed lipid peroxidation can induce apoptosis or necrosis leading to renal injury. This study examined whether low concentrations of cisplatin induce apoptosis in LLC-PK1 cells and whether caspases 1, 2, 3, 8, and 9 are activated during this event. Our results show a dose- and time-dependent induction of apoptosis by micromolar concentrations of cisplatin. Expression of oncogenes c-myc and p53 was induced, and except for caspase 1, all the other caspases tested were activated. Z-VAD, the broad-spectrum inhibitor of caspases, prevented caspase activation and apoptosis, but not c-myc and p53 induction. On the other hand, N-acetylcysteine prevented cisplatin-induced apoptosis as well as c-myc induction but not p53 induction. The antioxidant trolox also prevented cisplatin-induced apoptosis. The results suggest that antioxidants and caspase inhibitors may alleviate cisplatin-associated nephrotoxicity.

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.