A Meta-Analysis and Cohort Study of Histopathologic and Clinical Outcomes in ANCA-Negative versus -Positive Vasculitis.

BACKGROUND: ANCA-negative pauci-immune glomerulonephritis (PIGN) represents a rare and often under-studied subgroup of the vasculitides. This study aims to investigate differences in the clinical phenotype, renal histological features, and clinical outcomes of patients with PIGN, with and without serum ANCA positivity. METHODS: A cohort of biopsy-proven PIGN with and without detectable circulating ANCA was constructed from a single center between 2006 and 2016. Primary outcomes compared clinical presentation and histopathological features according to ANCA status, with multivariate Cox regression to compare mortality and ESKD. A systematic review and meta-analysis of the published literature was undertaken. RESULTS: In our cohort of 146 patients, 22% (n=32) had ANCA-negative disease, with a comparatively younger mean age at diagnosis; 51.4 versus 65.6 years (P<0.001). In total, 14 studies, inclusive of our cohort, were eligible for meta-analysis, totaling 301 patients who were ANCA negative. Those with ANCA-negative disease tended to have fewer extrarenal symptoms and a higher frequency of renal-limited disease, but both failed to reach statistical significance (P=0.92 and P=0.07). The risk of ESKD was significantly higher in seronegative disease (RR, 2.28; 95% confidence interval, 1.42 to 3.65; P<0.001), reflecting our experience, with a fivefold increased risk of ESKD in ANCA-negative disease (P<0.001). No significant difference in the chronicity of histopathological findings was seen and the meta-analysis showed no difference in morality (RR, 1.22; 95% confidence interval, 0.63 to 2.38; P=0.55). CONCLUSION: Our findings demonstrate that ANCA-negative PIGN presents in younger patients, with fewer extrarenal manifestations and higher ESKD risk, despite a lack of difference in histopathology. This study provides the impetus for further research into the pathogenesis, treatment response, and duration of immunotherapy in ANCA-negative disease. We suggest that the absence of positive ANCA serology should not discourage treatment and for clinical trials to include patients who are ANCA negative.

Automated Computational Detection of Disease Activity in ANCA-Associated Glomerulonephritis Using Raman Spectroscopy: A Pilot Study.

Biospectroscopy offers the ability to simultaneously identify key biochemical changes in tissue associated with a given pathological state to facilitate biomarker extraction and automated detection of key lesions. Herein, we evaluated the application of machine learning in conjunction with Raman spectroscopy as an innovative low-cost technique for the automated computational detection of disease activity in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis (AAGN). Consecutive patients with active AAGN and those in disease remission were recruited from a single UK centre. In those with active disease, renal biopsy samples were collected together with a paired urine sample. Urine samples were collected immediately prior to biopsy. Amongst those in remission at the time of recruitment, archived renal tissue samples representative of biopsies taken during an active disease period were obtained. In total, twenty-eight tissue samples were included in the analysis. Following supervised classification according to recorded histological data, spectral data from unstained tissue samples were able to discriminate disease activity with a high degree of accuracy on blind predictive modelling: F-score 95% for >25% interstitial fibrosis and tubular atrophy (sensitivity 100%, specificity 90%, area under ROC 0.98), 100% for necrotising glomerular lesions (sensitivity 100%, specificity 100%, area under ROC 1) and 100% for interstitial infiltrate (sensitivity 100%, specificity 100%, area under ROC 0.97). Corresponding spectrochemical changes in paired urine samples were limited. Future larger study is required, inclusive of assigned variables according to novel non-invasive biomarkers as well as the application of forward feature extraction algorithms to predict clinical outcomes based on spectral features.

Current-use pesticides in seawater and their bioaccumulation in polar bear-ringed seal food chains of the Canadian Arctic.

The distribution of current-use pesticides (CUPs) in seawater and their trophodynamics were investigated in 3 Canadian Arctic marine food chains. The greatest ranges of dissolved-phase concentrations in seawater for each CUP were endosulfan sulfate (less than method detection limit (MDL) to 19 pg L(-1) ) > dacthal (0.76-15 pg L(-1) ) > chlorpyrifos (less than MDL to 8.1 pg L(-1) ) > pentachloronitrobenzene (less than MDL to 2.6 pg L(-1) ) > α-endosulfan (0.20-2.3 pg L(-1) ). Bioaccumulation factors (BAFs, water-respiring organisms) were greatest in plankton, including chlorothalonil (log BAF = 7.4 ± 7.1 L kg(-1) , mean ± standard error), chlorpyrifos (log BAF = 6.9 ± 6.7 L kg(-1) ), and α-endosulfan (log BAF = 6.5 ± 6.0 L kg(-1) ). The largest biomagnification factors (BMFs) were found for dacthal in the capelin:plankton trophic relationship (BMF = 13 ± 5.0) at Cumberland Sound (Nunvavut), and for ß-endosulfan (BMF = 16 ± 4.9) and α-endosulfan (BMF = 9.3 ± 2.8) in the polar bear-ringed seal relationship at Barrow and Rae Strait (NU), respectively. Concentrations of endosulfan sulfate exhibited trophic magnification (increasing concentrations with increasing trophic level) in the poikilothermic portion of the food web (trophic magnification factor = 1.4), but all of the CUPs underwent trophic dilution in the marine mammal food web, despite some trophic level-specific biomagnification. Together, these observations are most likely indicative of metabolism of these CUPs in mammals. Environ Toxicol Chem 2016;35:1695-1707. © 2016 SETAC.

Trophodynamics of current use pesticides and ecological relationships in the Bathurst region vegetation-caribou-wolf food chain of the Canadian Arctic.

The bioaccumulation of current use pesticides (CUPs) and stable isotopes of carbon and nitrogen were investigated in vegetation-caribou-wolf food chain in the Bathurst region (Nunavut, Canada). Volumetric bioconcentration factors (BCF(v)) in vegetation were generally greatest for dacthal (10-12) ≥ endosulfan sulfate (10-11) > ß-endosulfan (>9.0-9.7) ≥ pentachloronitrobenzene (PCNB; 8.4-9.6) > α-endosulfan (8.3-9.3) > chlorpyrifos (8.0-8.7) >chlorothalonil (7.6-8.3). The BCF(v) values in vegetation were significantly correlated with the logarithm of the octanol-air partition coefficients (log K(OA)) of CUPs (r(2) = 0.90, p = 0.0040), although dacthal was an outlier and not included in this relationship. Most biomagnification factors (BMFs) for CUPs in caribou:diet comparisons were significantly less than 1. Similarly, the majority of wolf:caribou BMFs were either significantly less than 1 or were not statistically greater than 1. Significant trophic magnification factors (TMFs) were all less than 1, indicating that these CUPs exhibit trophic dilution through this terrestrial food chain. The log K(OA) reasonably predicted bioconcentration in vegetation for most CUPs but was not correlated with BMFs or TMFs in mammals. Our results, along with those of metabolic studies, suggest that mammals actively metabolize these CUPs, limiting their biomagnification potential despite entry into the food chain through effective bioconcentration in vegetation.