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Characteristics of glomerular crescent formation according to renal pathology
Source publication
Pauci-immune glomerulonephritis (GN) is an important cause of crescentic GN, acute renal failure and mortality. However, data are limited on the clinical presentation and outcome in antineutrophil cytoplasmic antibody (ANCA) negative patients, especially in Asians.
This retrospective study analyzed medical records and pathology slides of patients w...
Contexts in source publication
Context 1
... the 88 biopsies with glomerular crescents, five categories of renal pathology were identi- fied. However, definite diagnoses could not be made in five patients because of extensive fibro- sis (Table 2). Pauci-immune GN (n = 42) was the commonest diagnosis of renal pathology with glomerular crescents, accounting for nearly 50% of cases. ...
Context 2
... Renal survival of GN patients with glomerular crescents was poorer than that of GN patients without glomerular crescents (Figure 1). Progres- sion to end-stage renal disease (ESRD) occurred in 43 patients, accounting for 48.9% of patients with glomerular crescents (Table 2). Multivariate analysis showed that development of ESRD was associated with more extensive glomerular cres- cents (p < 0.001) and chronic glomerular lesions (p = 0.002) compared to other more favorable renal outcomes. ...
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Citations
... The finding of seronegative pauci-immune glomerulonephritis (PIGN) has previously reported to occur in up to 30% of cases (4)(5)(6). This was the case in both European and South East Asian cohorts, with data spanning several decades. ...
... Birmingham vasculitis activity scores (BVAS) were not included due to the presence of mainly renal limited disease and the limitations of retrospective scoring. 6 6 ...
... At the end of follow up, a higher proportion of ANCA negative progressed to ESKD (53.1% vs 11.7%). The hazard ratio (HR) for ESKD in ANCA negative patients compared to ANCA positive was 6 in ANCA negative patients. There was no significant difference in follow up duration between the two groups (P=0.09). ...
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.
... Remaining patients can have ANCA negative pauci-immune crescentic glomerulonephritis. [4,5,6] ANCA negative status has been documented in 10-39% patients with pauci-immune crescentic glomerulonephritis in various studies across the world with variation in the clinical, pathologic features and renal outcomes as compared to ANCA associated glomerulonephritis. [4,5,6,7,8] Present study is undertaken to study and compare the clinical, renal biopsy ndings and prognostic systems (Berden's histological classi cation, Brix's renal risk categories) in patients with ANCA negative and ANCA positive pauci-immune crescentic glomerulonephritis and to determine the patient and renal survival. ...
... [4,5,6] ANCA negative status has been documented in 10-39% patients with pauci-immune crescentic glomerulonephritis in various studies across the world with variation in the clinical, pathologic features and renal outcomes as compared to ANCA associated glomerulonephritis. [4,5,6,7,8] Present study is undertaken to study and compare the clinical, renal biopsy ndings and prognostic systems (Berden's histological classi cation, Brix's renal risk categories) in patients with ANCA negative and ANCA positive pauci-immune crescentic glomerulonephritis and to determine the patient and renal survival. ...
... Similar observations have been made by earlier studies with a decade earlier presentation in ANCA negative patients as compared to ANCA positive counterparts. [4,7,8,16] In our study as compared to ANCA positive patients lesser number of ANCA negative patients had systemic involvement in the form of fever, nasal and pulmonary involvement. Chen al have also observed lower prevalence of fever weight loss, arthralgia, upper respiratory tract and pulmonary involvement in ANCA negative PICN. ...
Introduction: Pauci-immune crescentic glomerulonephritis (PICN) is an important cause of rapidly progressive renal failure. 10-40% of PICN cases have ANCA negative serology. Present study compared clinico-pathologic features, Brix’s renal risk score, Berden’s histopathological classes and differences in outcome between ANCA-ve vs ANCA+ve PICN.
Methods: 61 patients of biopsy proven PICN were studied. Biochemical finding and ANCA serology were recorded. Renal biopsies slides were reviewed along with direct Immunofluorescence. Clinical and histological features were compared between ANCA negative and positive PICN using Man Whitney U test and chi square test. Patients were compared for distribution in Berden’s histological classes and Brix’s renal risk categories. Patient and renal survival were compared using Kaplan Meier survival analysis.
Results: ANCA negative PICN patients were younger (44.9±16.5year vs 53.6±15.1 year,p=0.049). Nasal(0 vs 18%,p=0.035) and pulmonary involvement(9% vs 38%,p=0.014) were lower in ANCA negative group. Both ANCA groups had similar renal biochemical profile, percentage normal glomeruli, 16.27±18.25vs21.69±20.42 and percentage glomeruli with crescents, 64.45±28.12vs64.25±27.11. 27% ANCA negative cases fell in the sclerotic class in Berden’s classification vs just 2.5% in ANCA positive group(p=0.037) without significant difference in Brix’s renal risk categories(p=0.329).13% of ANCA –ve patients achieved complete remission on treatment compared to 33% in ANCA +ve patients. Patient survival and overall probability of progressing to ESRD were similar in the two groups.
Conclusion: ANCA negative PICN cases present at younger age. Nasal and pulmonary involvement is uncommon with fewer cases achieving remission on treatment. Patient survival and progression to ESRD is similar in both ANCA groups.
... Current approaches in clinical practice use two main biomarkers to help predict potential relapse; ANCA and B-cell population, however their clinical utility remains limited. Persisting ANCA positivity, ANCA reappearance and anti-PR3 associated disease have been associated with a higher rate of relapse [22][23][24][25] , but despite this a significant proportion of de-novo and relapsing disease occurs in the absence of detectable circulating ANCA [26][27][28][29][30] , particularly amongst patients with extra-renal disease 31 . The significance of rising titres also remains debateable 32,33 . ...
The current lack of a reliable biomarker of disease activity in anti-neutrophil cytoplasmic autoantibody (ANCA) associated vasculitis poses a significant clinical unmet need when determining relapsing or persisting disease. In this study, we demonstrate for the first time that attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy offers a novel and functional candidate biomarker, distinguishing active from quiescent disease with a high degree of accuracy. Paired blood and urine samples were collected within a single UK centre from patients with active disease, disease remission, disease controls and healthy controls. Three key biofluids were evaluated; plasma, serum and urine, with subsequent chemometric analysis and blind predictive model validation. Spectrochemical interrogation proved plasma to be the most conducive biofluid, with excellent separation between the two categories on PC2 direction (AUC 0.901) and 100% sensitivity (F-score 92.3%) for disease remission and 85.7% specificity (F-score 92.3%) for active disease on blind predictive modelling. This was independent of organ system involvement and current ANCA status, with similar findings observed on comparative analysis following successful remission-induction therapy (AUC > 0.9, 100% sensitivity for disease remission, F-score 75%). This promising technique is clinically translatable and warrants future larger study with longitudinal data, potentially aiding earlier intervention and individualisation of treatment.
... Majority of the patients under this study were females (61.9%), which may be attributed to the particular ethnic profile of the population studied. Chen et al., [2] Hedger et al., [7] Eisenberger et al., [8] Hung et al., [9] and Jain et al., [10] have, however, reported no particular sexual predilection. ...
... More number of ANCA-negative patients belonged younger age groups compared to ANCA-positive patients as has been reported by Chen et al., [2] Eisenberger et al., [8] Hung et al., [9] and Jain et al. [10] Hedger et al. [7] , however, observed a comparable age. ...
... Maintenance therapy includes low-level immunosuppression with low dose glucocorticoids with or without rituximab. There are no studies comparing the treatment for ANCA positive and ANCA negative vasculitis [2,17]. Therefore, the same treatment protocols are used in ANCA negative patients. ...
Granulomatosis with polyangiitis (GPA) is a vasculitis of small and medium-sized vessels and presents with varying signs and symptoms. It includes upper and lower airway manifestations and glomerulonephritis with a positive antineutrophil cytoplasmic antibody (ANCA) in serology in 90% of cases. However, about 10% of cases with GPA can have negative serology, often resulting in a diagnostic delay. Obtaining a tissue pathology is needed to confirm GPA. Here we present a 77-year-old male who presented with generalized weakness and loss of appetite and was found to have glomerulonephritis and bilateral opacities in the lungs with a negative ANCA. He was diagnosed with ANCA negative granulomatosis with polyangiitis after a renal biopsy revealed necrotizing inflammation with crescent formation. He was successfully treated with systemic glucocorticoids and rituximab. In conclusion, prompt diagnosis and treatment of ANCA negative vasculitis are required to decrease mortality.
... However, it was also detected in a small number of patients with type I and II CrGN. It was reported that patients with negative ANCA had better renal outcomes (8,28,29). However, others have reported that patients without ANCA had higher levels of proteinuria, more severe glomerular lesions and poorer renal outcomes (8). ...
Rapidly progressive glomerulonephritis (RPGN), characterized by rapid kidney dysfunction caused by aggressive glomerulonephritis, is usually associated with crescentic glomerulonephritis (CrGN). In the present study, the data from patients with CrGN were retrospectively analyzed at a tertiary medical center in China with the aim of investigating the clinicopathological features and the association of the type of CrGN with the prognosis. The renal biopsies of 49 patients diagnosed with CrGN were obtained between December 2011 and July 2016. Of the 49 patients, 11 patients (22.45%) had type I CrGN, 19 (38.78%) had type II CrGN and 19 (38.78%) had type III CrGN. The majority of CrGN patients exhibited multiple-system involvement and 28 patients (57.14%) had kidney enlargement. Proportions of patients with acute kidney injury (AKI), acute kidney diseases without AKI, and chronic kidney disease were 28.57, 46.94 and 24.49%, respectively. Among the 3 types of CrGN, patients with type I CrGN tended to have a higher proportion of AKI with more cellular crescent formation, and higher serum creatinine and retinol binding protein. Circulating anti-GBM antibodies were present in all type I CrGN patients and anti-neutrophilic cytoplasmic autoantibodies were detected in 84.21% of patients with type III CrGN. Type III CrGN patients had a superior kidney survival, whereas type I CrGN patients had the worst kidney prognosis (P<0.001). There was no significant difference in overall patient survival among the 3 types of CrGN. CrGN remains the primary cause of critical illness in RPGN patients. There was much heterogeneity between the different subtypes of CrGN. Patients with type I tended to have an acute onset and had the poorest kidney survival.
... In these cases, though histologically renal damage may be extensive, the renal outcome after treatment is more significantly related to the serum creatinine at first consultation, and those with severe renal disease remained dialysis dependent [1][2][3][4][5][6][7][8][9][10]. Studies have shown renal outcome to be poor in ANCA-negative cases with very less probability for becoming dialysis-free [4,11]. The negative prognostic factors for the renal outcome for CGN in general are: Glomerular Filtration Rate (GFR) <15 mL/ min, advancing age, higher Birmingham Vasculitis Activity Score (BVAS), low hemoglobin and higher WBC count [1]. ...
Anti-Neutrophil Cytoplasmic Antibody (ANCA)-negative Rapidly Progressive Glomerulonephritis (RPGN) is a severe form of autoimmune renal injury with a bleak prognosis. A 60-year-old Indian woman was treated with classical homeopathy for ANCA-negative RPGN, and after one year of treatment, serum creatinine and other parameters indicating renal injury dropped steadily despite the withdrawal of immunosuppressive drugs; renal dialysis, which was conducted twice a week initially, was made rarer and stopped after one year. Classical homeopathy may be considered a potential therapeutic modality in severe pathologies. Controlled studies are required to establish further the extent to which classical homeopathy may relieve patients from procedures such as dialysis that cause considerable physical and economic discomfort.
... Renal survival was also worse in ANCA-negative patients compared to ANCA-positive patients (p < 0.05). Hung et al. [7] reported in their subgroup analysis of pauciimmune glomerulonephritis that ANCA-negative subjects had more chronic glomerular lesions compared to ANCA-positive patients who had more acute glomerular lesions. The chronicity of the renal disease in ANCA-negative patients is likely responsible for their poor treatment response and worse renal prognosis. ...
Anti-neutrophil cytoplasmic antibodies (ANCA) play an important role in the pathogenesis of pauci-immune renal vasculitis. However, in 10% of the cases, ANCA are absent. We present a case of a 64-year-old man with a chronic untreated hepatitis C virus infection and Middle Eastern thalassemia who was ANCA-negative when he was hospitalized due to acute kidney injury and accounts for an uncommon presentation of renal vasculitis. The patient had earlier reported to have undergone local lobectomy and adjuvant chemotherapy (carboplatin/pemetrexed) for lung adenocarcinoma a month prior. IL-6 has been reported to be involved in the pathophysiological cascade causing pauci-immune glomerulonephritis amongst non-small cell lung cancer patients. Previous studies with subgroup analysis have demonstrated that ANCA negativity has been associated with more chronic glomerular lesions and less crescent formation, which tends to have a critical outcome in the renal system. However, our patient underwent kidney biopsy exhibiting active crescentic glomerulonephritis, pauci-immune type with 5 cellular crescents amongst 15 glomeruli. To our knowledge, this is the third reported case of ANCA-negative vasculitis with typical presentation on biopsy in non-small cell lung cancer patients.
... [13] Studies in the past showed a higher degree of proteinuria and greater prevalence of nephrotic syndrome with more severe glomerular lesions in ANCA negative group when compared to ANCA positive group. [8,9,15] Immunosuppression is the mainstay of treatment for ANCA associated pulmonary-renal syndrome and Goodpasture's syndrome. High dose intravenous steroids for 3-5 days have been used commonly to achieve remission and are sometimes combined with oral or intravenous cyclophosphamide. ...
Rationale:
Pulmonary renal syndrome (PRS) is a term most commonly used to describe a combination of glomerulonephritis and pulmonary hemorrhage as a manifestation of a multisystem autoimmune disease. It is usually associated with ANCA vasculitis and anti-GBM disease. Diffuse alveolar hemorrhage in a patient with ANCA and anti-GBM negative pauci-immune glomerulonephritis is rare and optimal management is unknown.
Patient concerns:
An 85-year-old man with hypertension, diabetes mellitus, prostate cancer and recently diagnosed pauci-immune necrotizing glomerulonephritis presented to our emergency department with worsening dyspnea and pedal edema for several days. Clinical presentation and radiological studies were suggestive of fluid overload but he developed worsening respiratory failure despite hemodialysis.
Diagnoses:
Bronchoscopy confirmed diffuse alveolar hemorrhage. ANCA and anti-GBM antibodies were negative. The patient was diagnosed with pulmonary renal syndrome - diffuse alveolar hemorrhage in the setting of ANCA and anti-GBM negative pauci-immune glomerulonephritis.
Interventions:
Patient was started on intravenous pulse steroids, cyclophosphamide and received seven sessions of plasmapheresis.
Outcomes:
There was an improvement in patient's respiratory status and repeat bronchoscopy at the end of treatment did not show diffuse alveolar hemorrhage.
Lessons:
Pauci-immune crescentic necrotizing glomerulonephritis is usually associated with the presence of ANCA, however, ANCA may be absent in 10% of these cases. Immunosuppression is the mainstay of treatment for ANCA and anti-GBM associated PRS. This case highlights the importance of immunosuppression and plasmapheresis in patients with ANCA negative vasculitis due to presence of unidentified serum antibodies. If left untreated, these patients can have a fulminant course with high mortality ranging from 25 to 50%.
... ANCA negative patients were mainly from the focal and crescentic groups (48% and 37.5%, respectively). It was reported previously that a pauci-immune glomerulonephritis with negative antibody test is associated with the crescentic group and with a worse renal outcome [16][17][18]. However, we have not found any association between ANCA negativity and an unfavourable patient or renal outcome. ...
Background: Recently proposed histopathological classification may predict patient outcome in pauci-immune glomerulonephritis. This study sought to prove that the prognostic effect could be extended to all types of rapidly progressive glomerulonephritis. Methods: Retrospective analysis of patients diagnosed with rapidly progressive glomerulonephritis between April 1999 and August 2015 was performed. Epidemiological and clinical data were collected from medical records. The descriptions of renal biopsies were reviewed and classified into focal, sclerotic, crescentic and mixed class according to classification proposed by Berden et al. The study end points were end stage renal disease (ESRD) or death. Survival analyses were modelled using Cox regression. Results: 73 renal biopsies with diagnosis of rapidly progressive glomerulonephritis were included in the study. 25 (34.2%), 16 (21.9%), 24 (32.9%) and 8 (11%) patients were assigned to focal, crescentic, mixed and sclerotic class, respectively. Thirty-two (42.5%) patients were anti-neutrophil cytoplasmic antibody (ANCA) negative, of which eight (10.9%) were anti–glomerular basement membrane antibody (anti–GBM) positive and 24 (32.8%) were negative for autoimmune antibodies. Six (8.2%) patients died within one year. Among patients who survived, median change in estimated glomerular filtration rate (eGFR) values were: −10.5 mL/min in focal, 4.2 mL/min in crescentic, −4.3 mL/min in mixed and 4.1 mL/min in sclerotic group, p > 0.05. In the Cox regression model, there was no significant predictor of patient survival whereas the sclerotic group (HR 3.679, 95% CI, 1.164–11.628, p < 0.05) and baseline eGFR of <15 mL/min (HR 4.832, 95% CI, 1.55–15.08, p < 0.01) had an unfavorable effect for renal survival. Conclusions: Predominant glomerular sclerosis and low eGFR at baseline are associated with higher risk of ESRD in cases with crescentic glomerulonephritis. Therefore, despite the origin of injury, histological classification might aid in prediction of patient outcomes in rapidly progressive glomerulonephritis.
