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.

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.

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.

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.

Algunas consideraciones sobre la valoración de procainamida clorhidrato / Appraisement of procainamide hydrochloride

Se estudian métodos y alternativas para la determinación del contenido de procainamida clorhidrato, materia prima. Se realiza un análisis acerca de la influencia del anhídrico acético cuando se valora este fármaco anhidrovolumétricamente y se recomienda el método que de acuerdo con los ensayos efectuados y su evaluación estadística demostró ser el más eficiente, preciso, sencillo y rápido

Algunas consideraciones sobre la valoración de procainamida clorhidrato / Appraiseent of procainamide hydrochloride

Se estudian métodos y alternativas para la determinación del contenido de procainamida clorhidrato, materia prima. Se realiza un análisis acerca de la influencia del anhídrico acético cuando se valora este fármaco anhidrovolumétricamente y se recomienda el método que de acuerdo con los ensayos efectuados y su evaluación estadística demostró ser el más eficiente, preciso, sencillo y rápido

Acido salicílico libre en aspirina tabletas: evolución temporal; estudio colaborativo / Free salicylic acid in aspirin tablets: temporal evolution; colaborative study

Se demuestra mediante su aplicación durante un período de aproximadamente 2 años la factibilidad de establecer sistemáticamente la técnica espectrofotométrica usada para el control de calidad de la aspirina, hallándose su error sistemático (0,02 %) comprendidos los efectos inter e intralaboratorios y se comprobó estadísticamente su concordancia con buena aproximación con respecto al método oficial (USP XXI). La evolución del contenido de ácido salicílico en las muestras objeto de estudio permite recomendar el envase 817 mL y el uso de la materia prima designada "I". De acuerdo con los resultados obtenidos debe esperarse un contenido de salicílico libre inferior a los límites oficiales, al menos, durante año y medio en las condiciones actuales y con las recomendaciones antes mencionadas

Acido salicílico libre en aspirina tabletas. evolución temporal; estudio colaborativo / Free salicylic acid in aspirin tablets: teporal evolution; colaborative study

Se demuestra mediante su aplicación durante un período de aproximadamente 2 años la factibilidad de establecer sistemáticamente la técnica espectrofotométrica usada para el control de calidad de la aspirina, hallándose su error sistemático (0,02

) comprendidos los efectos inter e intralaboratorios y se comprobó estadísticamente su concordancia con buena aproximación con respecto al método oficial (USP XXI). La evolución del contenido de ácido salicílico en las muestras objeto de estudio permite recomendar el envase 817 mL y el uso de la materia prima designada "I". De acuerdo con los resultados obtenidos debe esperarse un contenido de salicílico libre inferior a los límites oficiales, al menos, durante año y medio en las condiciones actuales y con las recomendaciones antes mencionadas