Crescentic Class Research Articles

Pathological severity determines the renal recovery for anti-myeloperoxidase antibody-associated vasculitis requiring dialysis at disease onset: a retrospective study

BackgroundMany patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) need dialysis at disease onset due to severe kidney injury. Determining whether they can become dialysis independent is an important clinical assessment.MethodsForty kidney biopsy-proved myeloperoxidase (MPO)-ANCA associated AAV patients who required dialysis at disease onset were enrolled. Relationships between laboratory and pathological characteristics and prognoses were analyzed.ResultsTwenty-five patients obtained dialysis independence within 3 months, while the other 15 patients remained dialysis dependent. No sclerotic class was identified among the 40 patients. Only two biopsies exhibited focal class diagnoses and both these patients recovered their renal function. The renal recovery rate of the 20 patients with mixed class was significantly lower than that of the 18 patients with crescentic class (40.0% vs. 83.3%, p = 0.006). Receiver operating characteristics (ROC) curves showed fibrous crescent+global glomerulosclerosis greater than 32.6% was a strong predictor of dialysis dependence with a sensitivity of 93.3% and specificity of 88.0%. When the percentage of fibrous crescent+global glomerulosclerosis exceeded 47.9%, dialysis independence was not possible. Correlation analysis indicated that platelet counts were negatively correlated with the percentage of fibrous crescent+global glomerulosclerosis (R = -0.448, p = 0.004). Most patients with increased platelets (84.62%) obtained renal recovery. Compared with methylprednisolone pulse therapy, plasma exchange accelerated renal recovery (29.4 ± 15.6 vs. 41.4 ± 11.7 days, p = 0.039).ConclusionsFor MPO-ANCA AAV who required dialysis at disease onset, crescentic and mixed classes accounted for the majority of patients in our cohort. The renal outcome of mixed class patients was worse than that of crescentic class. A high proportion of fibrous crescent+global glomerulosclerosis is a predictor of dialysis dependence. Increased platelet count is associated with active and reversible renal lesions.

The expression of NOD2, NLRP3 and NLRC5 and renal injury in anti-neutrophil cytoplasmic antibody-associated vasculitis

BackgroundNucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are intracellular sensors of pathogens and molecules from damaged cells to regulate the inflammatory response in the innate immune system. Emerging evidences suggested a potential role of NLRs in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study aimed to investigate the expression of nucleotide-binding oligomerization domain containing protein 2 (NOD2), NOD-like receptor family pyrin domain containing 3 (NLRP3) and NOD-like receptor family CARD domain containing 5 (NLRC5) in kidneys of AAV patients, and further explored their associations with clinical and pathological parameters.MethodsThirty-four AAV patients in active stage were recruited. Their renal specimens were processed with immunohistochemistry to assess the expression of three NLRs, and with double immunofluorescence to detect NLRs on intrinsic and infiltrating cells. Analysis of gene expression was also adopted in cultured human podocytes. The associations between expression of NLRs and clinicopathological parameters were analyzed.ResultsThe expression of NOD2, NLRP3 and NLRC5 was significantly higher in kidneys from AAV patients than those from normal controls, minimal change disease or class IV lupus nephritis. These NLRs co-localized with podocytes and infiltrating inflammatory cells. The mean optical density of NOD2 in glomeruli was significantly higher in crescentic class than non-crescentic class, and correlated with levels of proteinuria and serum creatinine at renal biopsy. The mean optical density of NLRC5 in glomeruli was significantly higher in crescentic class than non-crescentic class, and correlated with proteinuria level, Birmingham Vasculitis Activity Score and the proportion of crescents in the renal specimen.ConclusionsThe expression of three NLRs was upregulated in kidneys of AAV patients. The expression of NOD2 and NLRC5 was associated with the severity of renal lesions in AAV.

Risk Factors for Renal Survival in Chinese Patients with Myeloperoxidase-ANCA-Associated GN.

Our study explored the association of histopathologic classification of ANCA-associated GN with renal survival in Chinese patients with myeloperoxidase-ANCA-associated GN. Two hundred fifteen patients with biopsy-proven myeloperoxidase-ANCA-associated GN were included from January of 1996 to December of 2014. The biopsies included focal (n=27), mixed (n=82), crescentic (n=47), and sclerotic (n=59) classes. The long-term renal outcome and risk factors of myeloperoxidase-ANCA-associated GN for different histopathologic classes were retrospectively analyzed. During a median follow-up time of 22 (9-51) months, 88 (40.9%) patients reached ESRD. The 5-year renal survival (overall 58.7%) was highest in the focal class (100.0%) and lowest in the sclerotic class (20.7%), with no difference between the mixed (58.9%) and crescentic (67.4%) classes. Patients in the mixed (hazard ratio, 0.34; 95% confidence interval, 0.20 to 0.57; P<0.001) and crescentic (hazard ratio, 0.31; 95% confidence interval, 0.16 to 0.59; P<0.001) classes were at lower risk for ESRD compared with patients in the sclerotic class, as were patients who received glucocorticoids plus mycophenolate mofetil (hazard ratio, 0.32; 95% confidence interval, 0.18 to 0.60; P<0.001) compared with those receiving glucocorticoids alone. In addition, patients with a serum creatinine level ≥4 mg/dl (hazard ratio, 2.93; 95% confidence interval, 1.77 to 4.85; P<0.001) or hypoalbuminemia (hazard ratio, 2.11; 95% confidence interval, 1.32 to 3.34; P=0.002) were at higher risk for ESRD. A serum creatinine level ≥4 mg/dl and a percentage of global sclerotic glomeruli ≥60% were the two independent risk factors for ESRD in the sclerotic class. The histopathologic classification of ANCA-associated GN in combination with serum creatinine and serum albumin levels and treatment regimen is associated with renal outcome in myeloperoxidase-ANCA-associated GN. The evaluation of serum creatinine level and percentage of global sclerotic glomeruli provides additional information on the risk of renal survival in the sclerotic class of myeloperoxidase-ANCA-associated GN.

Differences in the frequency of macrophage and T cell markers between focal and crescentic classes of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis.

BackgroundAnti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (AAGN) can be classified into; focal, crescentic, mixed and sclerotic classes. Macrophages and T lymphocytes are key players in mediating renal injury. The frequency of macrophage and T lymphocytes in different histological classes is unclear.ObjectivesWe examined the frequency of macrophage and T lymphocyte markers in AAGN and assessed their correlation with renal function at presentation.Patients and MethodsRenal biopsies from 38 patients were included in immunohistochemistry analysis of macrophages (CD68, sialoadhesin [Sn] and mannose receptor [MR]) and T cells (CD4 and CD8) markers. The frequency of these markers in glomerular, periglomerular and interstitial compartments were measured in a blinded fashion. Biopsies were allocated a histological class of focal, crescentic, mixed or sclerotic. Scores were then matched to histological class and assessed for correlation with renal function.ResultsThe biopsies were crescentic 19 (50%), focal 10 (26.3%), mixed 6 (15.7%) and sclerotic 3 (8%). Interstitial CD68+ macrophages and CD8+ T lymphocytes showed best correlation with renal function at the time of presentation. CD68+ macrophages were significantly increased in crescentic compared to focal AAGN. MR+ macrophages, CD4 and CD8 T cells were also elevated in the interstitium of crescentic compared to focal group.ConclusionsIn this study interstitial CD68 and CD8 showed the highest association with the renal function at presentation. Differences in the cellular infiltrate between focal and crescentic AAGN were related to CD68+ macrophages and to interstitial MR+ macrophages and T lymphocytes. Further studies are needed to assess these differences across all four histological categories.

Histopathological Classification and Renal Outcome in Patients with Antineutrophil Cytoplasmic Antibodies-associated Renal Vasculitis: A Study of 186 Patients and Metaanalysis.

Renal vasculitis is one of the most common manifestations of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) and renal histology is a key predictor of the outcome. A new histopathologic classification was proposed and validated, but the results are still debated. We performed a retrospective analysis to validate the histopathologic classification and performed a metaanalysis to evaluate its predictive value. There were 186 patients with ANCA-associated renal vasculitis diagnosed at Ruijin Hospital who were enrolled in the retrospective study. The metaanalysis considered the data for 1601 patients. In our retrospective study, patients with focal class had the best renal outcome while patients with mixed class had the worst (p < 0.001). Metaanalysis showed that patients with focal class had better renal outcome than did those with crescentic class [risk ratio (RR) 0.23, 95% CI 0.16-0.34, p < 0.00001], with no evidence of heterogeneity (I2 = 0%, p = 0.96). Patients with crescentic class had better renal outcome than did those with sclerotic class (RR 0.52, 95% CI 0.41-0.64, p < 0.00001), with no evidence of heterogeneity (I2 = 2%, p = 0.43). We did not find statistical significance regarding renal outcome between mixed and crescentic classes (RR 1.14, 95% CI 0.91-1.43, p = 0.27), with no evidence of heterogeneity (I2 = 23%, p = 0.19). The retrospective study showed that lung and upper respiratory tract involvement were the most common extrarenal manifestations. We demonstrated the clinical utility of histopathologic classification in determining renal outcome in patients with AAV. Metaanalysis showed that patients with focal class had the best outcome while sclerotic class had the worst.

Prognostic Value of Histologic Classification of ANCA-Associated Glomerulonephritis.

A kidney biopsy is preferred for the diagnosis of ANCA-associated vasculitis with renal involvement. The aim of our study was to evaluate the prognostic value of a histopathologic classification scheme recently proposed by an international consortium of renal pathologists in a large Norwegian cohort. Patients diagnosed with ANCA-associated GN were included from the Norwegian Kidney Biopsy Registry 1991-2012. Renal morphology was classified as focal, mixed, crescentic, or sclerotic. Study end point was ESRD. Patients were followed from kidney biopsy to end of 2012. Two hundred fifty patients with ≥10 glomeruli in the biopsy were included in our study. During a median follow-up of 3.5 years (0.7-7.6), 60 cases of ESRD occurred. Ninety-six (38%) biopsies were classified as focal, 61 (24%) biopsies were classified as mixed, 71 (28%) biopsies were classified as crescentic, and 22 (9%) biopsies were classified as sclerotic; 1- and 5-year cumulative renal survival rates were 96% and 90%, respectively, for the focal class, 86% and 75%, respectively, for the mixed class, 81% and 69%, respectively, for the crescentic class, and 56% and 51%, respectively, for the sclerotic class. By multivariate Cox regression analyses, the sclerotic class had a significantly worse renal prognosis than the focal (hazard ratio, 9.65; 95% confidence interval, 2.38 to 39.16) or combined mixed/crescentic classes (hazard ratio, 3.27; 95% confidence interval, 1.41 to 7.61), but no significant differences in outcome were observed in the crescentic class compared with the mixed class (hazard ratio, 1.13; 95% confidence interval, 0.44 to 2.87) or the combined mixed/crescentic class compared with the focal class (hazard ratio, 1.93; 95% confidence interval, 0.61 to 6.12). Accuracy by receiver operator characteristic curve analysis was estimated to be 0.72 (95% confidence interval, 0.65 to 0.80). In 108 additional patients with three to nine glomeruli in the biopsy, the prognostic value of this classification scheme was unchanged. The histopathologic classification is a predictor of renal outcome of moderate quality. Merging the mixed and crescentic classes in the future could simplify the scheme.

Predictors of renal histopathology in antineutrophil cytoplasmic antibody associated glomerulonephritis

ObjectivesPrompt, aggressive therapy is vital for anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. In this regard, we aimed to identify predictors of distinct renal histopathological classes at the time of clinical diagnosis. Patients & methodsAn inception cohort of patients with biopsy proven ANCA-associated glomerulonephritis was studied retrospectively. Demographics, clinical, laboratory, serological and radiological parameters were analyzed. Patients were classified on the basis of renal histopathology. A risk score was developed for each histopathological class using univariate and stepwise logistic regression analyses. ResultsVariables independently associated with focal class included disease duration up to diagnosis <8 weeks, absence of erythrocyte casts by urine microscopy and eGFR >49 ml/min/1.73 m2; with crescentic class >40 erythrocytes/hpf, identification of erythrocyte casts in urine, upper respiratory tract involvement and eGFR <49 ml/min/1.73 m2; with mixed class age >54 years, male gender, and absence of upper respiratory tract involvement. In the presence of these risk factors a predictive risk score for each histopathological classes was calculated: odds ratio, 95% confidence intervals (CI), for focal class (≥2 risk factors, 20.8 (95% CI: 5.1–84.2), p < 0.0001, and 441.0 (95% CI: 16.8–11,590), p = 0.0003 for crescentic class (≥3 risk factors) while the small number of patients in the mixed and sclerotic class precluded any estimates. ConclusionWe propose a predictive algorithm of specific histolopathological classes of ANCA-associated glomerulonephritis, which might provide a crude estimation of the disease activity in the glomeruli at presentation. This tool might assist the clinician in making decisions regarding the level of intensity of inductive immunosuppressive therapy at clinical diagnosis.

Pauci-immune glomerulonephritis: does negativity of anti-neutrophilic cytoplasmic antibodies matters?

A significant proportion of pauci-immune glomerulonephritis (PIGN) patients are reported to have absence of anti-neutrophilic cytoplasmic antibodies (ANCA). However, studies are controversial regarding their significance and there is limited data after the new prognostic classification of PIGN. Renal biopsy-proven cases of PIGN were included and their clinical details, ANCA status by immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA), Birmingham Vasculitis Activity Score (BVAS) and treatment outcomes at 6 months were noted. The renal biopsies were classified according to the proposed histopathological classification. Scoring was done from 0-3 for interstitial edema, interstitial fibrosis and tubular atrophy (IFTA), interstitial inflammation and arteriosclerosis. The percentage of glomeruli with sclerosis, cellular and fibrous crescents, and percentage of subjects with glomerulitis, tuft necrosis, interstitial granuloma and vasculitis were noted. Out of the 84 subjects included in the study, 33 (39.3%) were negative for ANCA by both IIF and ELISA. These subjects had significantly higher renal involvement, less extra-renal manifestations and lower BVAS. On histology, they had significantly higher proportion of crescentic class (66.7% vs. 41.2%, P = 0.039), higher number of cellular crescents (66.12% vs. 53.3%, P = 0.00008), higher IFTA (1.53 vs. 1.02, P = 0.009) and less interstitial edema (1.44 vs. 1.96, P = 0.003). The treatment outcomes were worse in ANCA-negative PIGN subjects, with significantly less improvement (37.2% vs. 62.8%, P = 0.02), more deterioration (40.7% vs. 14%, P = 0.006), and reduced probability of becoming dialysis free (31.6% vs. 69.6% P = 0.009). A negative ANCA in PIGN is associated with crescentic class, more IFTA and poor treatment outcomes.

Validation of a histopathologic classification scheme for antineutrophil cytoplasmic antibody-associated glomerulonephritis.

Antineutrophil cytoplasmic antibody-associated small-vessel vasculitides cause multiple organ system disease including rapidly progressive glomerulonephritis. Recently, Berden et al (J Am Soc Nephrol. 2010;21:1628-1636) proposed a new histopathologic classification scheme separating renal biopsies into 4 classes: focal, crescentic, mixed, and sclerotic. We validated the prognostic implications of this classification scheme in a retrospective cohort study of 67 individuals with antineutrophil cytoplasmic antibody glomerulonephritis who underwent kidney biopsy in Calgary, Alberta, between 2005 and 2010. Their biopsies were rescored according to the classification scheme of Berden et al. Additional tubulointerstitial parameters were also scored. Clinical information including demographics and creatinine values at presentation and 1-year follow-up was retrieved. The mean age was 60 years. Forty-one percent were female. Biopsies were classified as follows: 35% crescentic, 32% mixed, 21% focal, and 11% sclerotic. Ten patients (14%) died within 1 year. Among surviving patients, the overall mean (95% confidence interval) change in estimated glomerular filtration rate (eGFR) at 1 year was 11 (7-15) mL/min per 1.73 m(2), and this change significantly differed (P = .02) between the classes: 19 (11-27) mL/min per 1.73 m(2) with crescentic histology, 11 (1-21) mL/min per 1.73 m(2) with focal, 8 (3-13) mL/min per 1.73 m(2) with mixed, and -4 (-7 to -1) mL/min per 1.73 m(2) with sclerotic. Tubulointerstitial pathology parameters did not predict outcomes. Patients with crescentic class biopsies showed significantly more improvement in eGFR at 1 year compared with the mixed (P = .04) and sclerotic (P = .005) classes. The focal class was associated with the highest eGFR values at presentation and 1 year. These findings validate the prognostic utility of the Berden classification scheme and suggest that it may be generalizable.

Validation of the new classification of pauci-immune glomerulonephritis in a United States cohort and its correlation with renal outcome

BackgroundRenal biopsies provide important diagnostic and prognostic information in ANCA associated glomerulonephritis. A new classification for prognostication of pauci-immune glomerulonephritis (GN) based on four categories (Mixed, Crescentic, Sclerotic and Focal) was proposed by an international working group of renal pathologists (IWGRP). The goal of our study was to apply the proposed classification system to a United States cohort of vasculitis patients and determine the association of IWGRP class with estimated glomerular filtration rate (eGFR) at one year.MethodsSeventy-six cases of pauci-immune glomerulonephritis diagnosed from 1995 to 2011 from a single center were identified for this retrospective study. Clinical data were collected by abstraction from medical records. Histology was reviewed by a pathologist and classified according to the new classification. MDRD formula was used to calculate eGFR. We correlated IWGRP class to renal function at presentation and at one year. ×2, ANOVA, and linear regression analysis were performed as appropriate.ResultsRenal biopsies were categorized as focal: n = 20, crescentic: n = 18, mixed: n = 27, sclerotic: n = 11. The baseline e-GFR was lowest in the crescentic class and highest in the focal class. In linear regression analysis investigating e-GFR at 1 year; age and baseline e-GFR were independent predictors of e-GFR at 1 year.ConclusionsThe e-GFR at diagnosis and age were predictors of e-GFR at 1 year. Pathologic class at diagnosis may also be a helpful tool in risk stratification at diagnosis.