Exploring source differences on diet-tissue discrimination factors in the analysis of stable isotope mixing models.

Stable isotope mixing models are regularly used to provide probabilistic estimates of source contributions to dietary mixtures. Whilst Bayesian implementations of isotope mixing models have become prominent, the use of appropriate diet-tissue discrimination factors (DTDFs) remains as the least resolved aspect. The DTDFs are critical in providing accurate inferences from these models. Using both simulated and laboratory-based experimental data, this study provides conceptual and practical applications of isotope mixing models by exploring the role of DTDFs. The experimental study used Mozambique Tilapia Oreochromis mossambicus, a freshwater fish, to explore multi-tissue variations in isotopic incorporation patterns, and to evaluate isotope mixing model outputs based on the experiment- and literature-based DTDFs. Isotope incorporation patterns were variable for both muscle and fin tissues among the consumer groups that fed diet sources with different stable isotope values. Application of literature-based DTDFs in isotope mixing models consistently underestimated the dietary proportions of all single-source consumer groups. In contrast, application of diet-specific DTDFs provided better dietary estimates for single-source consumer groups. Variations in the proportional contributions of the individual sources were, nevertheless, observed for the mixed-source consumer group, which suggests that isotope assimilation of the individual food sources may have been influenced by other underlying physiological processes. This study provides evidence that stable isotope values from different diet sources exhibit large variations as they become incorporated into consumer tissues. This suggests that the application of isotope mixing models requires consideration of several aspects such as diet type and the associated biological processes that may influence DTDFs.

Environmental niche patterns of native and non-native fishes within an invaded African river system.

To test ecological niche theory, this study investigated the spatial patterns and the environmental niches of native and non-native fishes within the invaded Great Fish River system, South Africa. For the native fishes, there were contrasting environmental niche breadths that varied from being small to being large and overlapped for most species, except minnows that were restricted to headwater tributaries. In addition, there was high niche overlap in habitat association among fishes with similar distribution. It was therefore inferred that habitat filtering-driven spatial organisation was important in explaining native species distribution patterns. In comparison, most non-native fishes were found to have broad environmental niches and these fishes showed high tolerance to environmental conditions, which generally supported the niche opportunity hypothesis. The proliferation of multiple non-native fishes in the mainstem section suggest that they form a functional assemblage that is probably facilitated by the anthropogenic modification of flow regimes through inter-basin water transfer. Based on the distribution patterns observed in the study, it was inferred that there was a likelihood of negative interactions between native and non-native fishes. Such effects are likely to be exacerbated by altered flow regime that was likely to have negative implications for native ichthyofauna.

Innate responses to conspecific and heterospecific alarm cues in the endangered eastern cape redfin Pseudobarbus afer.

We examined innate responses to conspecific and heterospecific alarm cues in a small cyprinid minnow, the Eastern Cape redfin Pseudobarbus afer. We found that redfins respond to conspecific skin extract, which contains alarm chemicals, and showed that their preferred response is to hide in refugia. Redfins also respond to skin extract from an allopatric, distantly related minnow species, the chubbyhead barb Enteromius anoplus indicating that neither sympatry nor close phylogenetic relationships are necessary for recognition of heterospecific alarm cues. Although both conspecific and heterospecific alarm cues induced similar responses, the response to heterospecific cues was less intense. This may be explained by a trade-off between selection to maximise threat recognition and selection to avoid the costs of responding to irrelevant cues, or by differences in chemical structures of alarm cues between species. These findings have implications for the conservation of this Endangered fish species and for freshwater fishes throughout Africa.

Ocean warming, a rapid distributional shift, and the hybridization of a coastal fish species.

Despite increasing awareness of large-scale climate-driven distribution shifts in the marine environment, no study has linked rapid ocean warming to a shift in distribution and consequent hybridization of a marine fish species. This study describes rapid warming (0.8 °C per decade) in the coastal waters of the Angola-Benguela Frontal Zone over the last three decades and a concomitant shift by a temperature sensitive coastal fish species (Argyrosomus coronus) southward from Angola into Namibia. In this context, rapid shifts in distribution across Economic Exclusive Zones will complicate the management of fishes, particularly when there is a lack of congruence in the fisheries policy between nations. Evidence for recent hybridization between A. coronus and a congener, A. inodorus, indicate that the rapid shift in distribution of A. coronus has placed adults of the two species in contact during their spawning events. Ocean warming may therefore revert established species isolation mechanisms and alter the evolutionary history of fishes. While the consequences of the hybridization on the production of the resource remain unclear, this will most likely introduce additional layers of complexity to their management.

Alternative responses to predation in two headwater stream minnows is reflected in their contrasting diel activity patterns.

Animals exhibit diel periodicity in their activity in part to meet energy requirements whilst evading predation. A competing hypothesis suggests that partitioning of diel activities is less important because animals capitalise on opportunity. To test these hypotheses we examined the diel activity patterns for two cyprinid minnows, chubbyhead barb Barbus anoplus and the Eastern Cape redfin minnow Pseudobarbus afer that both occur within headwater streams in the Eastern Cape, South Africa. Chubbyhead barbs exhibited consistent nocturnal activity based on both field and laboratory observations. Due to the absence of fish predators within its habitat, its nocturnal behaviour suggests a response to the cost associated with diurnal activity, such as predation risk by diving and wading birds. In contrast, redfin minnows showed high diurnal activity and a shoaling behaviour in the wild, whereas, in the laboratory, they showed high refuge use during the diel cycle. Despite their preference for refuge in the laboratory, they were diurnally active, a behaviour that was consistent with observations in the wild. The diurnal activity of this species suggests a response to the cost associated with nocturnal activity. Such a cost could be inferred from the presence of the longfin eel, a native predator that was active at night, whereas the daytime shoaling behaviour suggests an anti-predator mechanism to diurnal visual predators. The implications of these findings relate to the impacts associated with the potential invasions by non-native piscivores that occur in the mainstem sections. Diurnal activity patterns for redfin minnows, that are IUCN-listed as endangered, may, in part, explain their susceptibility to high predation by visual non-native piscivores, such as bass and trout. In contrast, the nocturnal habits of chubbyhead barbs suggest a probable pre-adaptation to visual predation. The likelihood of invasion by nocturnally-active sharptooth catfish Clarias gariepinus, however, may compromise this prior advantage.

Oral dose-ranging developmental toxicity study of an herbal supplement (NT) and gallic acid in rats.

OBJECTIVE: To evaluate the combination of rhubarb, astragalus, red sage, ginger, and turmeric (mixture referred to as "NT") together with gallic acid for evidence of reproductive toxicity in rats. METHODS: Fifty virgin female rats were cohabited with male rats. Day 0 of potential pregnancy was evidence of spermatozoa on vaginal smear. The presumably pregnant rats were randomized to five groups of 10 individuals and were fed by daily gavage on days 6-20 of presumed gestation with one of the following: deionized water placebo, 21.6 mg/kg per day, 215 mg/kg per day, 430 mg/kg per day, or 860 mg/kg per day of a mixture of NT (20%) and gallic acid (80%). Cesarean section was performed on day 21. RESULTS: All 50 rats had one or more live fetuses and survived until they were killed. Body weight was reduced in the 860 mg/kg per day group compared with placebo: mean (SD), 406.8 (23.0) vs. 430.1 (27.7) g, P<0.05. There were no dose-related adverse events or differences between groups in uterine size, food intake, corpora lutea, implantations, litter size, number of live fetuses, and gender distribution of fetuses or fetal resorptions. There were no dead fetuses, and all placentae appeared normal. All rats and tissues were normal at necropsy. Fetal weights did not differ between groups, and there were no fetal abnormalities. CONCLUSION: The combination of NT and gallic acid gave no evidence of reproductive toxicity at 430 mg/kg per day or below, which is reassuring should this combination be used in the future as a dietary herbal supplement for the treatment of obesity.

Prospective study of TNFalpha blockade with adalimumab in ANCA-associated systemic vasculitis with renal involvement.

BACKGROUND: Tumour necrosis factor alpha (TNFα) is implicated in the pathogenesis of ANCA-associated systemic vasculitis (AASV). There is a need for more effective and safer induction therapies for AASV. Uncontrolled studies have pointed to the efficacy of TNFα blockade with infliximab in the induction of remission in systemic vasculitides. We have hypothesized that adjunctive treatment with the humanized anti-TNFα monoclonal antibody, adalimumab, will permit more rapid remission and reduced prednisolone exposure in AASV. METHODS: This Phase II, open-label, prospective study enrolled 14 patients with acute flares of AASV either as first manifestation of disease or relapse. The Birmingham Vasculitis Activity Score (BVAS) was used to assess the activity of the disease and the response to treatment. Adalimumab (40 mg s.c.) was given every 2 weeks for 3 months, in combination with intravenous cyclophosphamide and a reducing course of prednisolone. Primary endpoints were: (i) induction of remission within the first 14 weeks (BVAS = 0); (ii) time taken to achieve remission; (iii) safety and tolerability. RESULTS: Mean age was 58 years and eight patients were male; all had kidney involvement. Eleven (78.5%) achieved remission within 14 weeks (mean, 12 weeks). BVAS decreased from 11.9 (mean; 95% CI, 9.3-14.4) at baseline to 2.0 (mean; 95% CI, 0-4.4) at Week 14 (P < 0.01). Prednisolone dose (in milligrammes per day) decreased from 37.1 (mean; 95% CI, 28.8-45.3) at entry to 8.1 (mean; 95% CI, 5.1-11.1) at Week 14 (P < 0.01). Estimated glomerular filtration rate (in millilitres per minute per 1.73 m(2)) increased from 17.1 (mean; 95% CI, 8.9-25.2) at entry to 30.1 (mean; 95% CI, 18-42.2) at 12 weeks (P < 0.01). One patient died and three infections occurred. CONCLUSIONS: The addition of adalimumab to prednisolone and cyclophosphamide for the treatment of severe AASV was associated with response rates and adverse events similar to standard therapy alone but with a reduced prednisolone exposure. Further study is required to demonstrate whether the addition of adalimumab improves the speed of remission, the degree of renal recovery and safety.

Differential microvasculature dysfunction in living kidney donor transplant recipients: nondialyzed versus dialyzed chronic kidney disease patients.

We hypothesized that there was differential vasomotor dysfunction in the microcirculation between nondialyzed and dialyzed chronic kidney disease (CKD) patients. During live donor kidney transplantation procedures, skin arterioles (SkA; internal diameter = 120 +/- 5 microm) from donors (n = 27) and recipients (nondialysis = 15; dialysis = 20) were dissected from the abdominal wall at the incision site. In vivo aortic pulse wave velocity (PWV) was also measured. In the in vitro isometric force measurement, nondialyzed SkA exhibited comparable contraction to donor SkA, whereas dialyzed SkA had 60 and 40-50% increase in contraction in response to depolarization and agonist (that is, phenylephrine, serotonin and endothelin-1) stimulation, respectively. The acetylcholine-induced relaxation in the nondialyzed SkA was decreased by 50% compared with dialyzed SkA. However, pre-incubation with superoxide dismutase greatly enhanced the relaxation response in the nondialyzed, but not in the dialyzed SkA and donor SkA. Pre-incubation with N(G)-nitro-L-arginine methyl ester (L-NAME) elevated the resting tension and left-shifted the concentration response curve of phenylephrine-stimulated contraction in the donor-SkA. L-NAME only increased the resting tension in the nondialyzed vessel. In vitro stiffness positively correlated with PWV (R(2) = 0.302, p = 0.001), and dialyzed SkA was 60% stiffer than nondialyzed and donor SkA. The acetylcholine relaxation was negatively correlated with PWV in donors and recipients (R(2) = 0.282, p = 0.01). In conclusion, we have uniquely demonstrated differential microvasculature dysfunction between nondialyzed and dialyzed CKD patients.

Inducible nitric oxide synthase activity is increased in patients with rheumatoid arthritis and contributes to endothelial dysfunction.

BACKGROUND: Recent in vitro studies suggest that inducible nitric oxide synthase (iNOS) activity mediates endothelial dysfunction. Rheumatoid arthritis (RA) is a chronic inflammatory condition and is associated with endothelial dysfunction and increased risk of cardiovascular disease. The aim of the study was to establish the contribution of iNOS to endothelial function. METHODS: Forearm blood flow (FBF) was measured during intra-arterial infusions of acetylcholine (ACh), sodium nitroprusside (SNP), N(G)-monomethyl-l-arginine (l-NMMA) and aminoguanidine (AG) in 12 RA patients and 13 healthy control subjects. Levels of C-reactive protein (CRP) and myeloperoxidase (MPO) were assessed. FBF data are presented as mean percentage changes in the ratio (infused/control arm) of FBF + or - SEM. RESULTS: FBF response to ACh was reduced in patients with RA compared to controls (179 + or - 29 v. 384 + or - 72%, respectively; P=0.01), but SNP response was not (P=0.5). FBF response to AG differed between patients and controls (-15 + or - 2% v. 13 + or - 4%, respectively; P<0.001), whereas the response to l-NMMA did not (P=0.4). In a multiple regression model log CRP, AG response and LDL were found to be independent predictors of endothelial function (R(2)=0.617, P<0.001). CONCLUSION: RA patients have endothelial dysfunction and increased iNOS activity in comparison to controls. Furthermore, CRP and iNOS activity were independently associated with endothelial function. Our data demonstrates that inflammation is a key mediator in a process of endothelial dysfunction possibly via activation of iNOS and increased production of MPO.

Ezetimibe and simvastatin reduce inflammation, disease activity, and aortic stiffness and improve endothelial function in rheumatoid arthritis.

OBJECTIVES: The aim of this study was to investigate the effect of simvastatin and ezetimibe on inflammation, disease activity, endothelial dysfunction, and arterial stiffness in a cohort of rheumatoid arthritis (RA) patients. BACKGROUND: Rheumatoid arthritis is a chronic inflammatory condition associated with increased cardiovascular risk. Statins reduce inflammation and disease activity in RA patients, but whether this is due to pleiotropism or cholesterol lowering per se is unclear. METHODS: Twenty patients received 20 mg simvastatin or 10 mg ezetimibe each for 6 weeks in a randomized double-blind crossover study. Disease activity, blood pressure, aortic pulse wave velocity (PWV), brachial artery flow-mediated dilation (FMD), and serum inflammatory markers were measured before and after each treatment. RESULTS: Both ezetimibe and simvastatin significantly reduced total cholesterol (-0.62 +/- 0.55 mmol/l and -1.28 +/- 0.49 mmol/l, respectively; p < 0.001), low-density lipoprotein cholesterol (-0.55 +/- 0.55 mmol/l and -1.28 +/- 0.49 mmol/l; p < 0.0001), and C-reactive protein (-5.35 +/- 9.25 mg/l and -5.05 +/- 6.30 mg/l; p < 0.001). Concomitantly, Disease Activity Score (-0.55 +/- 1.01 and -0.67 +/- 0.91; p = 0.002), aortic PWV (-0.69 +/- 1.15 m/s and -0.71 +/- 0.71 m/s; p = 0.001), and FMD (1.37 +/- 1.17% and 2.51 +/- 2.13%; p = 0.001) were significantly improved by both drugs. CONCLUSIONS: This study demonstrates that both ezetimibe and simvastatin reduce disease activity and inflammatory markers to a similar extent in patients with RA. Therapy is also associated with a concomitant reduction in aortic PWV and improvement in endothelial function. This suggests that cholesterol lowering per se has anti-inflammatory effects and improves vascular function in RA.

Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction.

Isolated systolic hypertension is associated with increased cardiovascular risk. It is thought to result from large artery stiffening, which is determined by structural components within the vasculature but also by functional factors including NO and endothelin-1. We hypothesized that endothelial dysfunction would account for increased arterial stiffness in patients with isolated systolic hypertension. The aim of this study was to investigate the relationship between endothelial function and arterial stiffness in these patients along with control subjects. We studied 113 subjects: 35 patients with isolated systolic hypertension (mean age+/-SD: 68+/-6 years), 30 age-matched control subjects (65+/-5 years), and 48 young control subjects (37+/-9 years). Aortic pulse wave velocity (PWV) was derived by sequential carotid/femoral waveform recordings. Conduit artery endothelial function was determined by flow-mediated dilatation. Aortic PWV was higher (9.65+/-2.56 m/s versus 8.26+/-0.85 m/s; P=0.009), and flow-mediated dilatation was lower (2.67+/-1.64% versus 4.79+/-3.1%; P=0.03) in patients with isolated systolic hypertension compared with age-matched control subjects. Similarly, aortic PWV was also higher, and flow-mediated dilatation lower, in older versus young control subjects (8.26+/-0.85 m/s versus 7.09+/-1.01 m/s and 4.79+/-3.1% versus 6.94+/-2.7%; P=0.004 for both). Overall, aortic PWV correlated inversely with flow-mediated dilatation (r=-0.3; P=0.001), which remained significant after adjustment for confounding factors (P=0.01). Patients with isolated systolic hypertension have higher aortic PWV and decreased endothelial function compared with age-matched control subjects. Our results suggest that endothelial function contributes significantly to increased arterial stiffness in patients with isolated systolic hypertension and with age.

Rheumatoid arthritis is associated with increased aortic pulse-wave velocity, which is reduced by anti-tumor necrosis factor-alpha therapy.

BACKGROUND: Rheumatoid arthritis (RA) is associated with increased cardiovascular risk, which is not explained by traditional cardiovascular risk factors but may be due in part to increased aortic stiffness, an independent predictor of cardiovascular mortality. In the present study, our aim was to establish whether aortic stiffness is increased in RA and to investigate the relationship between inflammation and aortic stiffness. In addition, we tested the hypothesis that aortic stiffness could be reduced with anti-tumor necrosis factor-alpha (TNF-alpha) therapy. METHODS AND RESULTS: Aortic pulse-wave velocity (PWV), augmentation index, and blood pressure were measured in 77 patients with RA and in 142 healthy individuals. Both acute and chronic inflammatory measures and disease activity were determined. The effect of anti-TNF-alpha therapy on PWV and endothelial function was measured in 9 RA patients at 0, 4, and 12 weeks. Median (interquartile range) aortic PWV was significantly higher in subjects with RA than in control subjects (8.35 [7.14 to 10.24] versus 7.52 [6.56 to 9.18] m/s, respectively; P = 0.005). In multiple regression analyses, aortic PWV correlated independently with age, mean arterial pressure, and log-transformed C-reactive protein (R2 = 0.701; P < 0.0001). Aortic PWV was reduced significantly by anti-TNF-alpha therapy (8.82+/-2.04 versus 7.94+/-1.86 versus 7.68+/-1.56 m/s at weeks 0, 4, and 12, respectively; P < 0.001); concomitantly, endothelial function improved. CONCLUSIONS: RA is associated with increased aortic stiffness, which correlates with current but not historical measures of inflammation, suggesting that increased aortic stiffness may be reversible. Indeed, anti-TNF-alpha therapy reduced aortic stiffness to a level comparable to that of healthy individuals. Therefore, effective control of inflammation may be of benefit in reducing cardiovascular risk in patients with RA.

Tumor necrosis factor alpha blockade with infliximab for refractory uveitis and scleritis.

OBJECTIVE: To assess the efficacy and safety of the anti-tumor necrosis factor alpha agent infliximab in treatment-resistant uveitis and scleritis. DESIGN: Retrospective, noncomparative interventional case series. PARTICIPANTS: Seven patients with noninfectious ocular inflammatory disease that was refractory to alternative immunosuppression. These included one patient with idiopathic retinal vasculitis and panuveitis, one patient with intermediate uveitis, one patient with chronic juvenile anterior uveitis, three patients with scleritis, and one patient with scleritis and peripheral ulcerative keratitis. Four patients had an underlying systemic disease that was in remission in three cases. INTERVENTION: Infusions of infliximab, 200 mg, were given at 4-week to 8-week intervals, depending on the clinical response. MAIN OUTCOME MEASURES: Clinical response, including symptoms, visual acuity, degree of scleral vascular engorgement, corneal thinning, anterior chamber activity, and posterior segment inflammation, reduction in concomitant immunosuppression, and adverse effects. RESULTS: The mean patient age was 47 years (range, 24-78), and four patients were female. The mean number of infliximab infusions was seven (range, 2-19), and the mean follow-up period was 12 months (range, 4-22 months). Six patients experienced a clinical improvement, with five achieving remission and significant reduction in immunosuppression. One patient showed an initial response but developed a delayed hypersensitivity response that precluded further treatment. No other adverse effects occurred. CONCLUSIONS: Infliximab seems to be an effective and safe treatment for noninfectious uveitis and scleritis and may be indicated as rescue therapy for relapses of ocular inflammation or as maintenance therapy when conventional immunosuppression has failed. Further investigation of infliximab for treatment-resistant scleritis and uveitis is warranted.

Prospective study of TNFalpha blockade with infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis.

UNLABELLED: Tumor necrosis factor alpha (TNFalpha) plays an important role in the pathogenesis of anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. TNFalpha blockade is a potential therapy for these disorders. METHODS: An open-label, multi-center, prospective clinical trial in two subgroups was performed. Study I examined acute disease, either first presentation or relapse (Birmingham Vasculitis Activity Score [BVAS] > or = 10; n = 16); study II examined persistent disease (BVAS > or = 4; n = 16). Patients received infliximab (5 mg/kg) at 0, 2, 6, and 10 wk. Concomitant therapy in study I included prednisolone and cyclophosphamide. Study II patients continued their existing treatment regimens, with prednisolone tapered according to clinical status. RESULTS: Mean age was 52.4 yr, 53% of the patients were female, and follow-up was 16.8 mo. Twenty-eight patients (88%) achieved remission (14 per study group). BVAS decreased from 12.3 (confidence interval [CI] = 10.5 to 14.0) at entry to 0.3 (CI = 0.2 to 0.9) at wk 14 (P < 0.001). C-reactive protein (mg/L) decreased from 29.4 (CI = 16.8 to 42.0) at entry to 7.0 (CI = 3.3 to 10.9) by wk 14 (P = 0.001). Mean prednisolone dose (mg/d) in study II decreased from 23.8 (CI = 15.0 to 32.5) at entry to 8.8 (CI = 5.9 to 11.7) at wk 14 (P = 0.002). There were two deaths and seven serious infections. Relapse occurred in five patients (three in study II) after a mean of 27 wk. CONCLUSION: TNFalpha blockade with infliximab was effective at inducing remission in 88% of patients with antibody-associated systemic vasculitis and permitted reduction in steroid doses. Severe infections were seen in 21% of patients, and despite continued infliximab, 20% of initial responders experienced disease flares. Infliximab is a promising new therapy for vasculitis both as a component of initial therapy and in the management of refractory disease. These results need confirmation in larger randomized trials.

Immunotherapy for autoimmune and inflammatory renal diseases.

Immune-mediated renal disease (IMRD) accounts for 20 - 30% of the cases of end stage renal failure. It frequently occurs in the context of multi-system autoimmune disorders, including systemic lupus erythematosus (SLE) and primary systemic vasculitis. Current therapies are partially effective and comprise the combination of steroids with an immunosuppressive, such as cyclophosphamide. Their toxicity contributes to the morbidity and mortality of these disorders, and long-term treatment is necessary to prevent relapse. There is a clear need for better-targeted, more effective and less toxic therapy. Advances in our understanding of the immunopathogenesis of inflammatory autoimmune renal disease have identified potential targets for newer agents and have improved the monitoring of therapeutic responses. Recent experience with newer therapies in IMRD is reviewed. This has typically involved small, non-randomised, open-label trials and has addressed reversible features of disease activity. Larger, randomised comparisons to standard therapy are needed along with assessment of long-term efficacy and safety.

Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study.

BACKGROUND: Renal involvement is frequently present in antineutrophil cytoplasmic autoantibody (ANCA)-associated systemic vasculitis and is an important cause of end-stage renal failure (ESRF). METHODS: This retrospective, multicenter, sequential cohort study reports presenting features and outcome of 246 new patients diagnosed in London, UK, between 1995 and 2000. RESULTS: Diagnostic subgroups were microscopic polyangiitis, 120 patients (49%); Wegener's granulomatosis (WG), 82 patients (33%); renal-limited vasculitis, 33 patients (13.5%); and Churg-Strauss angiitis, 11 patients (4.5%). Median age was 66 years, 57% were men, and median creatinine level at presentation was 3.87 mg/dL (342 micromol/L). ANCA was present in 92%. Cumulative patient survival at 1 and 5 years was 82% and 76%, respectively. Mortality was associated with age older than 60 years (P < 0.001), development of ESRF (P < 0.001), initial creatinine level greater than 2.26 mg/dL (200 micromol/L; P = 0.01), and sepsis (P < 0.048). ESRF occurred in 68 patients (28%), of whom 47% died. Fifty-six patients who presented with a creatinine level greater than 5.65 mg/dL (500 micromol/L) survived, and 31 patients (55%) achieved dialysis independence. Relapse occurred in 34% after a median of 13 months and was more common in patients with WG (P = 0.048) and proteinase 3-ANCA (P = 0.034). Leukopenia occurred in 41% and was associated with sepsis (P < 0.001). CONCLUSION: Mortality and morbidity of ANCA-associated systemic vasculitis are improving compared with previous series, but remain high. Renal vasculitis often affects older patients, who have a particularly poor outcome. Early diagnosis improves outcome. Leukopenia, caused by immunosuppressive therapy, should be avoided because of the close association with sepsis and death.