Complement alternative pathway determines disease susceptibility and severity in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

Activation of the alternative pathway (AP) of complement is involved in the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), although the underlying molecular mechanisms are unclear. To gain insight into the role of the AP, common gene variants in CFH/CFHR1-5, CFB, C3 and MCP, and longitudinal determinations of plasma C3, C4, FH, FHR-1, FHR-2, FHR-5, FB, properdin and sC5b-9 levels were analyzed in a Spanish AAV cohort consisting of 102 patients; 54 with active AAV (active cohort) and 48 in remission not receiving immunosuppressants or dialysis therapy (remission cohort). The validation cohort consisted of 100 patients with ANCA-associated glomerulonephritis. Here, we demonstrated that common genetic variants in complement components of the AP are associated with disease susceptibility (CFB32Q/W) or severity of kidney damage in AAV (CFH-H1, CFH1H2 and ΔCFHR3/1). Plasma levels of complement components were significantly different between active and remission cohorts. In longitudinal observations, a high degree of AP activation at diagnosis was associated with worse disease outcome, while high basal FHR-1 levels and lower FH/FHR-1 ratios determined severe forms of kidney associated AAV. These genetic and plasmatic findings were confirmed in the validation cohort. Additionally, autoantibodies against FH and C3 convertase were identified in one and five active patients, respectively. Thus, our study identified key genetic and plasma components of the AP that determine disease susceptibility, prognosis, and severity in AAV. Our data also suggests that balance between FH and FHR-1 is critical and supports FHR-1 as a novel AP-specific therapeutic target in AAV.

Genetic testing in focal segmental glomerulosclerosis: in whom and when?

Background: Genetic causes are increasingly recognized in patients with focal segmental glomerulosclerosis (FSGS), but it remains unclear which patients should undergo genetic study. Our objective was to determine the frequency and distribution of genetic variants in steroid-resistant nephrotic syndrome FSGS (SRNS-FSGS) and in FSGS of undetermined cause (FSGS-UC). Methods: We performed targeted exome sequencing of 84 genes associated with glomerulopathy in patients with adult-onset SRNS-FSGS or FSGS-UC after ruling out secondary causes. Results: Seventy-six patients met the study criteria; 24 presented with SRNS-FSGS and 52 with FSGS-UC. We detected FSGS-related disease-causing variants in 27/76 patients (35.5%). There were no differences between genetic and non-genetic causes in age, proteinuria, glomerular filtration rate, serum albumin, body mass index, hypertension, diabetes or family history. Hematuria was more prevalent among patients with genetic causes. We found 19 pathogenic variants in COL4A3-5 genes in 16 (29.3%) patients. NPHS2 mutations were identified in 6 (16.2%) patients. The remaining cases had variants affecting INF2, OCRL, ACTN4 genes or APOL1 high-risk alleles. FSGS-related genetic variants were more common in SRNS-FSGS than in FSGS-UC (41.7% vs 32.7%). Four SRNS-FSGS patients presented with NPHS2 disease-causing variants. COL4A variants were the most prevalent finding in FSGS-UC patients, with 12 patients carrying disease-causing variants in these genes. Conclusions: FSGS-related variants were detected in a substantial number of patients with SRNS-FSGS or FSGS-UC, regardless of age of onset of disease or the patient's family history. In our experience, genetic testing should be performed in routine clinical practice for the diagnosis of this group of patients.

Anti-myeloperoxidase and proteinase 3 antibodies for nephritis flare prediction in anti-neutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: The value of myeloperoxidase (MPO) and proteinase 3 (PR3) antibody titres in the assessment of renal disease activity and flare prediction in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is not well known. METHODS: We performed a retrospective study including 113 AVV patients with renal biopsy-proven pauci-immune necrotizing glomerulonephritis from seven Spanish hospitals. The main inclusion criteria were assessment of MPO antibodies using multiplex flow immunoassay and PR3 antibody measurements using immunoassay chemiluminescence with an identical range of values for all participating centres. RESULTS: Serum MPO antibodies 3 ± 1.2 months before relapse were higher in patients who relapsed [19.2 ± 12.2 versus 3.2 ± 5.1 antibody index (AI); P < 0.001]. The discrimination value of MPO antibodies 3 months before renal relapse had an area under the receiver operating characteristics curve (AUC) of 0.82 [95% confidence interval (CI) 0.73-0.92; P < 0.001]. ΔMPO antibodies (change in antibodies titration 6 months before relapse) were higher in patients who relapsed (8.3 ± 12 versus 0.9 ± 3.1 AI; P = 0.001). The discrimination value of ΔMPO had an AUC of 0.76 (95% CI 0.63-0.88; P < 0.001). The positive predictive value of renal relapse in PR3 patients is 100% and the negative predictive value of renal relapse in patients with PR3-positive titres is 57.1%. Serum PR3 antibodies were higher in patients who relapsed 2.8 ± 1.4 months before relapse (58.6 ± 24.6 versus 2.0 ± 0.6 AI; P < 0.001). CONCLUSIONS: MPO level monitoring using multiplex flow immunoassay and PR3 measurements using immunoassay chemiluminescence are useful and sensitive tools for the prediction of renal relapse in the follow-up of AAV patients with renal disease and relevant surrogate markers of renal disease activity.

Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Toward an Individualized Approach.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), characterized by the presence of autoantibodies to neutrophil cytoplasmic antigens, proteinase 3 (PR3), and myeloperoxidase (MPO), typically involves small blood vessels of the respiratory tract and kidneys. It includes distinct clinical syndromes: microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic GPA. GPA is commonly associated with PR3-ANCA, while MPA is associated with MPO-ANCA. AAVs have a complex pathogenesis, influenced by genetics and environmental factors. There is evidence for a loss of tolerance to neutrophil proteins, which leads to ANCA-mediated neutrophil activation and injury, with effector T cells and activation of the alternative pathway of the complement also involved. Advances in immunosuppressive treatment have drastically reduced mortality of AAV in the past decades, opting for a more individualized approach. Careful assessment of ANCA specificity, disease activity, organ damage, and quality of life allows for a tailored immunosuppressive therapy. Contemporary AAV treatment is characterized by regimens that minimize the cumulative exposure to glucocorticoids and cyclophosphamide, and novel approaches including complement blockage and immunosuppressant combinations might be the standard of care in the future. In this review, we examine the pathogenesis, clinical approach, and evidence-based treatment options for the management of AAV patients.

Urinary soluble CD163 as a biomarker of disease activity and relapse in antineutrophil cytoplasm antibody-associated glomerulonephritis.

BACKGROUND: Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis is a chronic relapsing and remitting autoimmune disease. Urinary soluble CD163 (usCD163) has been proposed as a biomarker of active renal vasculitis. We aimed to assess the potential usefulness of usCD163 for diagnosing renal relapse in patients with ANCA-associated glomerulonephritis. METHODS: One hundred and fifty-six samples from 47 patients with ANCA-associated glomerulonephritis belonging to two different cohorts (incident and prevalent) and 20 healthy controls were studied. Patients from the incident cohort were prospectively followed up, and usCD163 concentrations were measured every 3 months. Renal relapses were identified and changes in usCD163 concentrations were analysed. RESULTS: Normalized usCD163 concentrations were elevated at disease onset in all patients with active renal vasculitis, with a median concentration of 601 ng/mmol (interquartile range 221-1404 ng/mmol). On the other hand, usCD163 concentrations were undetectable among control patients with renal vasculitis in remission. Except for non-responders, usCD163 concentrations progressively decreased in all patients after treatment. In the presence of vasculitis relapse, there was a consistent increase in usCD163 concentrations, compared with previous values. The area under the receiver-operating characteristic curve of absolute and relative changes in usCD163 concentrations to identify relapse of ANCA-associated glomerulonephritis was 0.96 [95% confidence interval (CI) 0.91-1.00; P = 0.001] and 0.95 (95% CI 0.90-1.00; P = 0.001), respectively. Sensitivity and specificity for a relative increase of 20%, or an absolute increase of 20 ng/mmol, in usCD163 concentrations were 100% for both, and 89.3% and 87.5%, respectively. Urinary sCD163 concentrations significantly correlated with Birmingham Vasculitis Activity Score scores at Month 6 (r = 0.737; P = 0.006) and Month 12 (r = 0.804; P = 0.005). CONCLUSIONS: usCD163 represents an accurate biomarker for the detection of active renal vasculitis and relapse. Its close association with disease activity provides additional information for monitoring treatment response.

Long-term validation of the renal risk score for vasculitis in a Southern European population.

BACKGROUND: Recently, renal risk score on the basis of three clinicopathologic features to predict end-stage renal disease (ESRD) in antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis has been proposed. The aim of this multi-centre study was to validate this renal risk score in a large cohort of southern European patients. METHODS: Data were retrospectively collected from the time of diagnosis by systematic review of medical records from 147 patients with renal vasculitis recruited from three Spanish centres. The renal risk score was calculated in every patient, and renal and global outcomes were analysed according to the risk group assessment. RESULTS: ANCA serology was positive in 76.2% of patients: 64.6% showed activity against myeloperoxidase (MPO) and 12.2% against proteinase 3 (PR3). The median (interquartile range) follow-up period was 41 months (9.6-104). Forty-eight patients (32.7%) reached ESRD. Patients were classified into the three groups according to the risk of progression to ESRD: 21.8% of patients were classified into low risk, 52.4% were classified into moderate risk and the remaining 25.9% were classified into high risk. The cumulative proportion of renal survival at 2, 5 and 10 years was 100, 100 and 82% in the low-risk group, 79, 77 and 77% in the medium-risk group and 63, 53 and 40% in the high-risk group (P < 0.001). In regression analysis, the risk score was a good predictor for the development of the ESRD among ANCA positive [hazard ratio (HR) = 2.7, 95% confidence interval (CI) 1.4-4.9; P < 0.001] and ANCA negative (HR = 2.7, 95% CI 1.04-7.1, P = 0.04) patients. CONCLUSIONS: The renal risk score constitutes an accurate tool to predict renal outcome among patients with renal vasculitis. This study contributes to validate the risk scoring system in a MPO-predominant population, but also among ANCA-negative vasculitis patients.

Towards a model for aerosol removal by rain scavenging: The role of physical-chemical characteristics of raindrops.

A one-year study was carried out in León, Spain, in order to characterize physically and chemically the precipitation. With the aim of studying the scavenging process of atmospheric pollutants, scavenging ratio and removal coefficients were calculated through physical parameters of raindrops (obtained by disdrometer data) and through chemical properties of aerosols. Finally, linear models for the prediction of the chemical composition of rainwater and the efficiency of the removal effect were established. In general, the rainwater was dominated by NH4+ > SO42- > NO3- in all seasons. Higher ion concentrations and conductivity and lowest pH were observed in summer, due to the low volume of rain. In winter, the high values of Na+ and Cl- in the rainwater showed the contribution from marine sources, while in summer the high concentrations of Ca2+, Mg2+, SO42-, NH4+ and NO3- reflected the contribution from both crustal and anthropogenic sources. The linear models revealed that the amount of dissolved organic carbon and of the water-soluble ions in rain samples, Ca2+, SO42-, NO3-, increases with the volume swept by the falling drops. Insoluble carbon fraction has a negative dependence with the volume swept and positive with the diameter of the raindrop. Removal coefficients are affected by the concentration in the air of each species before precipitation, the duration of the event and the time elapsed between two precipitation events.

Renal vasculitis presenting with acute kidney injury.

Renal failure secondary to ANCA-associated vasculitis represents a clinical and therapeutic challenge. In this study, we aimed to assess the treatment response rates and long-term outcomes of vasculitis patients presenting with renal failure. This retrospective study included 151 patients with renal vasculitis from three hospitals who underwent a renal biopsy between 1997 and 2014. Patients with renal failure which required dialysis at the onset were compared to those presenting with more preserved renal function. The primary end point was treatment response and patient surivival. Patients with severe renal involvement had a lower response to treatment compared to those having preserved renal function (26.6 versus 93.4%; p < 0.001). Dialysis-dependent patients who received plasmapheresis in addition to immune suppressants associated a higher rate of renal recovery (41.6 versus 12.5%; p = 0.05). A higher incidence of severe infections was observed among patients with severe renal involvement (38.4 versus 18.1%, p = 0.01). The mortality rate was significantly higher among vasculitis patients presenting with renal failure (53.8 versus 22.2%, p = 0.001). Global survival at 1 and 5 years was 60 and 47% in patients requiring dialysis compared with 90 and 80% among those with more preserved renal function (p < 0.001). After multivariate adjustment, the need for dialysis remained as an independent predictor of death (HR 2.5; 95% CI 1.1-5.7; p = 0.03). The presence of severe renal dysfunction represents an independent risk factor for patient survival in renal vasculitis. Patients requiring dialysis associate a lower response rate to immunosuppressive therapy and a higher incidence of severe infections.

Circulating C3 levels predict renal and global outcome in patients with renal vasculitis.

Several studies have demonstrated the crucial role of complement activation in the pathogenesis of ANCA-associated vasculitis. We aimed to assess the association between baseline serum C3 (sC3) levels and long-term outcomes in patients with renal vasculitis. This retrospective study included 111 patients with renal vasculitis from three hospitals who underwent a renal biopsy between 1997 and 2014. Serum levels of C3 were measured at the onset and the study population was divided into three tertiles according to sC3 concentrations (tertile 1 <106 mg/dl; tertile 2 106-128 mg/dl; tertile 3 >128 mg/dl). Patients with lower sC3 (tertile 1) were compared with those having higher levels of sC3 (tertile 2 and tertile 3). Histological, clinical, and laboratory data were recorded for analysis. The primary end point was the composite of end-stage renal disease (ESRD) and death from any cause. Lower sC3 levels were associated with a higher need for dialysis and lower response rate to treatment (p = 0.04 and p = 0.007, respectively). Renal and global survival at 1 and 5 years was 53 and 46 % in patients with lower sC3 (tertile 1) compared with 72 and 65 % in patients with higher sC3 (upper two tertiles) (p = 0.04). In a multivariate Cox-regression model, when adjusted by renal function and histopatholologic categories, lower sC3 remained as an independent predictor of ESRD and death (HR, 1.9; 95 % CI, 1.1 to 3.4; p = 0.02). Baseline serum C3 levels have an independent prognostic value in predicting long-term renal and global survival in patients with renal vasculitis.

Glomerular C3d as a novel prognostic marker for renal vasculitis.

Pauci-immune necrotizing crescentic glomerulonephritis is the histologic substrate of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Several studies in animal models have demonstrated the crucial role of complement activation in the pathogenesis of ANCA-associated vasculitis, but only small series have analyzed the prognostic implications of complement glomerular deposits. This study aimed to assess the clinical and prognostic implications of C3d- and C4d-positive glomerular staining in renal vasculitis. Eighty-five patients with a diagnosis of pauci-immune necrotizing crescentic glomerulonephritis were included in the study. C3d and C4d were analyzed by immunohistochemical staining using a polyclonal antibody. The primary predictors were glomerular C3d- and C4d-positive staining. The primary end point was the cumulative percentage of patients who developed end-stage renal disease. Glomerular staining for C3d and C4d was observed in 42 (49.4%) of 85 biopsies and 38 (44.7%) of 85 biopsies, respectively. C3d-positive staining was associated with the severity of renal impairment and with a lower response rate to treatment (P=.003 and P=.04, respectively). Renal survival at 2 and 5 years was 60.9% and 51.8% in C3d-positive patients compared with 87.7% and 78.9% in C3d-negative patients (P=.04). C4d-positive staining did not show any impact in renal outcome. When adjusted by renal function and other histologic parameters, C3d staining remained as an independent predictor for renal survival (hazard ratio, 2.5; 95% confidence interval, 1.1-5.7; P=.03). Therefore, this study demonstrates that C3d-positive glomerular staining is an independent risk factor for the development of end-stage renal disease in ANCA-associated renal vasculitis.

Therapeutic variability in adult minimal change disease and focal segmental glomerulosclerosis.

BACKGROUND: Variability in the management of glomerulonephritis may negatively impact efficacy and safety. However, there are little/no data on actual variability in the treatment of minimal change disease (MCD)/focal segmental glomerulosclerosis (FSGS) in adults. We assessed Spanish practice patterns for the management of adult nephrotic syndrome due to MCD or FSGS. The absence of reasonably good evidence on treatment for a disease often increases the variability substantially. Identification of evidence-practice gaps is the first necessary step in the knowledge-to-action cyclical process. We aim to analyse the real clinical practice in adults in hospitals in Spain and compare this with the recently released Kidney Disease: Improving Global Outcomes clinical practice guideline for glomerulonephritis. METHODS: Participating centres were required to include all adult patients (age >18 years) with a biopsy-proven diagnosis of MCD or FSGS from 2007 to 2011. Exclusion criteria included the diagnosis of secondary nephropathy. RESULTS: We studied 119 Caucasian patients with biopsy-proven MCD (n = 71) or FSGS (n = 48) from 13 Spanish hospitals. Of these patients, 102 received immunosuppressive treatment and 17 conservative treatment. The initial treatment was steroids, except in one patient in which mycophenolate mofetil was used. In all patients, the steroids were given as a single daily dose. The mean duration of steroid treatment at initial high doses was 8.7 ± 13.2 weeks and the mean global duration was 38 ± 32 weeks. The duration of initial high-dose steroids was <4 weeks in 41% of patients and >16 weeks in 10.5% of patients. We did find a weak and negative correlation between the duration of whole steroid treatment in the first episode and the number of the later relapses (r = -0.24, P = 0.023). There were 98 relapses and they were more frequent in MCD than in FSGs patients (2.10 ± 1.6 versus 1.56 ± 1.2; P = 0.09). The chosen treatment was mainly steroids (95%). Only seven relapses were treated with another drug as a first-line treatment: two relapses were treated with mycophenolate and five relapses were treated with anticalcineurinics. A second-line treatment was needed in 29 patients (24.4%), and the most frequent drugs were the calcineurin inhibitors (55%), followed by mycophenolate mofetil (31%). Although cyclophosphamide is the recommended treatment, it was used in only 14% of the patients. CONCLUSIONS: We found variation from the guidelines in the duration of initial and tapered steroid therapy, in the medical criteria for classifying a steroid-resistant condition and in the chosen treatment for the second-line treatment. All nephrologists started with a daily dose of steroids as the first-line treatment. The most frequently used steroid-sparing drug was calcineurin inhibitors. Cyclophosphamide use was much lower than expected.

Kidney injury after sodium phosphate solution beyond the acute renal failure / Daño renal después de preparación colónica con soluciones de fosfato. Más allá del fracaso renal agudo

Antecedentes y objetivos: La colonoscopia con polipectomía con fines de cribado reduce la incidencia del cáncer colorrectal y la mortalidad por esta enfermedad. Una preparación colónica aceptable es una de las claves para conseguir mejores resultados con esta técnica. Las soluciones de fosfato de sodio oral (OSP) fueron muy utilizadas en la década de los noventa del siglo pasado. Su eficacia era similar a la de las soluciones de polietilenglicol (PEG), pero más baratas y con una administración sencilla. Se han descrito series de casos de pacientes con insuficiencia renal aguda provocada por OSP. Sin embargo, en cohortes amplias de pacientes no se observó ninguna diferencia en la incidencia de daño renal entre estas dos soluciones. Métodos: Entre 2006 y 2009 identificamos 12 casos de nefropatía por fosfato tras preparación con OSP para colonoscopia. Se realizó el seguimiento de todos los pacientes durante 6 meses. Todos los pacientes habían recibido una única dosis. Resultados: Analizamos 12 casos de nefropatía por fosfato; 3 se manifestaron con IRA y 9 presentaron daño renal crónico. Cuatro de los casos se confirmaron mediante biopsia renal. Un paciente con IRA precisó hemodiálisis en el momento del diagnóstico, sin que experimentara recuperación posterior. Dos pacientes (ambos con daño crónico) recuperaron totalmente su función renal anterior. Los demás pacientes (9) presentaron una pérdida media en la filtración glomerular estimada de 24ml/min/1,73m2. Conclusiones: El uso de OSP puede ocasionar daño renal tanto agudo como crónico. Sin embargo, el daño crónico fue el más frecuente. Ambas formas de presentación suponen una pérdida considerable e irreversible de función renal. Nuevos estudios que analicen el daño renal secundario a preparación colónica deben considerar estos dos patrones distintos de daño (AU)

Background and objectives: Screening colonoscopy with polipectomy reduces colonorectal cancer incidence and mortality. An adequate bowel cleansing is one of the keys to achieving best results with this technique. Oral sodium phosphate solution (OSP) had a widespread use in the 90s decade. Its efficacy was similar to polyethylene glycol (PEG) solution, but with less cost and convenient administration. Series of patients with acute renal failure due to OSP use have been reported. However, large cohorts of patients found no difference in the incidence of renal damage between these two solutions. Methods: From 2006 to 2009 we identified twelve cases of phosphate nephropathy after colonoscopy prepared with OSP. All patients were followed up to six months. All patients had received just a single dose. Results: We analyzed 12 cases with phosphate nephropathy; three patients debuted with AKI and nine patients had chronic renal injury. Four cases were confirmed with renal biopsy. One patient with AKI needed hemodialysis at diagnosis without subsequent recovery. Two patients (both with chronic damage) fully recovered their previous renal function. The remaining patients (nine) had an average loss of estimated glomerular filtration rate of 24ml/min/1.73m2. Conclusions: The use of OSP can lead to both acute and chronic renal damage. However, chronic injury was the most common pattern. Both forms of presentation imply a significant and irreversible loss of renal function. Further studies analyzing renal damage secondary to bowel cleaning should consider these two different patterns of injury (AU)

Kidney injury after sodium phosphate solution beyond the acute renal failure.

BACKGROUND AND OBJECTIVES: Screening colonoscopy with polipectomy reduces colonorectal cancer incidence and mortality. An adequate bowel cleansing is one of the keys to achieving best results with this technique. Oral sodium phosphate solution (OSP) had a widespread use in the 90s decade. Its efficacy was similar to polyethylene glycol (PEG) solution, but with less cost and convenient administration. Series of patients with acute renal failure due to OSP use have been reported. However, large cohorts of patients found no difference in the incidence of renal damage between these two solutions. METHODS: From 2006 to 2009 we identified twelve cases of phosphate nephropathy after colonoscopy prepared with OSP. All patients were followed up to six months. All patients had received just a single dose. RESULTS: We analyzed 12 cases with phosphate nephropathy; three patients debuted with AKI and nine patients had chronic renal injury. Four cases were confirmed with renal biopsy. One patient with AKI needed hemodialysis at diagnosis without subsequent recovery. Two patients (both with chronic damage) fully recovered their previous renal function. The remaining patients (nine) had an average loss of estimated glomerular filtration rate of 24ml/min/1.73m(2). CONCLUSIONS: The use of OSP can lead to both acute and chronic renal damage. However, chronic injury was the most common pattern. Both forms of presentation imply a significant and irreversible loss of renal function. Further studies analyzing renal damage secondary to bowel cleaning should consider these two different patterns of injury.

The predictive value of kidney biopsy in renal vasculitis: a multicenter cohort study.

The histopathologic classification of antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated to have prognostic value in small cohorts of patients with pauci-immune extracapillary glomerulonephritis. We aimed to validate this histologic subgrouping system in a large cohort of patients with renal vasculitis from 3 Spanish centers. The additional value of several histologic parameters for predicting renal outcome was investigated. A total of 151 biopsies of patients with renal vasculitis were reviewed and classified as follows: 41% crescentic, 24% mixed, 21% focal, and 14% sclerotic. The cumulative proportions of renal survival at 5 years were 83.2%, 81.2%, 60.5%, and 50.7% for the focal, mixed, crescentic, and sclerotic categories, respectively (P < .05). In the crescentic category, patients with less than 75% of glomeruli showing crescents had better survival at 1 and 5 years compared with those having greater than or equal to 75% of crescents (77.9% and 70.6% versus 51.3% and 45.6%; P = .02). When adjusted by renal function and other histologic parameters, the percentage of extracapillary proliferation and glomerulosclerosis remained as significant predictors for renal survival (hazard ratio, 1.03; 95% confidence interval, 1.01-1.05; P = .001, and hazard ratio, 1.03; 95% confidence interval, 1.01-1.05; P = .002, respectively). In conclusion, patients with pauci-immune crescentic glomerulonephritis experienced different outcomes depending on the percentage of crescents observed, so that extensive extracapillary proliferation was associated with the poorest renal survival. These findings validate the prognostic utility of the histologic classification scheme in antineutrophil cytoplasmic antibody positive and negative patients and suggest a subdivision of crescentic category (<75% and ≥75% of crescents) based on the different survival rates observed among these subgroups.

Antineutrophil cytoplasmic antibody negative pauci-immune extracapillary glomerulonephritis.

AIM: Pauci-immune extracapillary glomerulonephritis (PEGN) is one of the most common causes of rapidly progressive glomerulonephritis and is usually associated with circulating anti-neutrophil cytoplasmic antibodies (ANCAs). However, a significant number of individuals with PEGN test negative for ANCA and this study aimed to analyze the characteristics of this subgroup of patients. METHODS: Patients from two centres who were diagnosed with PEGN between 1997 and 2014 were studied retrospectively. Clinicopathological characteristics and renal outcome were compared between patients presenting with pauci-immune necrotizing extracapillary glomerulonephritis associated or not with the presence of circulating ANCA. RESULTS: Among the 114 patients with PEGN, 29 (25.4%) were ANCA negative. Compared with the 85 ANCA-positive patients, ANCA-negative patients were younger at the onset (54.8 ± 17.2 vs. 62 ± 14.0 years; P < 0.05). The median level of urinary protein excretion was significantly higher among ANCA-negative patients (3.1 vs. 1 g/24 h; P < 0.001), whereas no differences were found in renal function and need for dialysis between ANCA-negative and positive groups. Extrarenal involvement was present independently of ANCA status. Histological analysis showed that ANCA-negative patients were more likely to have mesangial proliferation (P < 0.05). Renal and global survival were similar between ANCA-negative and positive patients, and treatment response and relapse rates were comparable in both groups. CONCLUSIONS: ANCA-negative pauci-immune extracapillary glomerulonephritis is not a rare condition and is part of a systemic vasculitis disease. Although ANCA-negative patients have renal and histological characteristics that differ from ANCA-positive patients, renal survival and treatment response in PEGN are independent of ANCA status.

Removal of tetracyclines from swine manure at full-scale activated sludge treatment plants.

The purpose of this study was to investigate the fate of three tetracyclines (TCs), namely oxytetracycline (OTC), chlortetracycline (CTC) and doxycycline (DC) at two different full-scale swine manure-activated sludge treatment plants. Throughout treatment, OTC, CTC and DC were removed by 71-76%, 75-80% and 95%, respectively. Removal of these TCs under physical treatment was deniable. On the contrary, the flocculation-coagulation and the secondary clarification resulted in a relevant reduction of the concentration of these TCs.