Histopathological classification of pauci immune glomerulonephritis and its impact on outcome

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1 DOI /s z ORIGINAL ARTICLE Histopathological classification of pauci immune glomerulonephritis and its impact on outcome Godasi S. R. S. N. K. Naidu Aman Sharma Ritambra Nada Harbir Singh Kohli Vivekanand Jha Krishan Lal Gupta Vinay Sakhuja Manish Rathi Received: 12 December 2013 / Accepted: 6 May 2014 / Published online: 18 May 2014 Springer-Verlag Berlin Heidelberg 2014 Abstract Rapidly progressive renal failure is a common but severe feature of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. A histopathological classification for ANCA-associated pauci-immune glomerulonephritis was developed for prognostication of these patients. The present study aims to classify patients of pauci-immune glomerulonephritis according to this classification and its impact on outcome. Eighty-six subjects with pauci-immune glomerulonephritis between July 2006 and October 2012 were included in the study. Their renal biopsies were reviewed and classified into focal, crescentic, sclerotic and mixed class as per the new classification. The outcomes were analyzed after 6 months of treatment. Of the 86 subjects, 34 (39.53 %) were granulomatosis with polyangiitis, 36 (41.86 %) microscopic polyangiitis, 1 eosinophilic granulomatosis with polyangiitis, while the rest (17.44 %) were unclassifiable. Thirteen (15.5 %), 43 (51.2 %), 12 (14.3 %) and 16 (19 %) patients were classified as focal, crescentic, sclerotic and mixed class, respectively. The mean serum creatinine at baseline was , , and µmol/l in focal, crescentic, sclerotic and mixed class, respectively. The probability of improvement in renal functions at 6 months decreased from G. S. R. S. N. K. Naidu H. S. Kohli V. Jha K. L. Gupta V. Sakhuja M. Rathi (*) Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh , India drmanishrathi2000@yahoo.co.in A. Sharma Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India R. Nada Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India focal to crescentic to mixed to sclerotic class, while the probability of death was highest in the sclerotic class followed by the mixed class. This difference in outcome was maintained irrespective of the clinical diagnosis or the Birmingham Vasculitis Activity Score. Our study has shown that the histopathological classification can be used to predict the severity of renal dysfunction as well as the treatment outcomes in pauci-immune glomerulonephritis. Keywords ANCA-associated vasculitis Pauci-immune glomerulonephritis Renal biopsy Rapidly progressive renal failure Introduction Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA, previously known as Wegener s granulomatosis), eosinophilic granulomatosis with polyangiitis (EGPA, previously known as Churg Strauss syndrome, CSS) and renal limited vasculitis. Rapidly progressive deterioration of renal function is a common and usually severe clinical feature of ANCA-associated vasculitis, which may lead to end-stage renal disease or death [1]. The morphologic changes in the renal biopsy are the gold standard for establishing a diagnosis of ANCA-associated glomerulonephritis, which is characterized by necrotizing and crescentic glomerulonephritis on light microscopy and the classical pauci-immune staining on immunofluorescence [2]. A new histopathological classification for ANCA-associated glomerulonephritis was developed by an international working group of renal pathologists in The classification has four general categories: focal, crescentic, sclerotic and mixed [2]. The first three categories are based on the

2 1722 Rheumatol Int (2014) 34: predominance of normal glomeruli, glomeruli with cellular crescents and globally sclerotic glomeruli, respectively. The mixed category represents a heterogeneous glomerular phenotype, where no glomerular feature predominates. Even before this classification, few clinico-pathological correlation studies showed that the prognosis in a patient with ANCA-associated glomerulonephritis is dependent on the age, initial creatinine levels, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), number of abnormal glomeruli, glomeruli with fibrous crescents and glomeruli with global sclerosis [1, 3 14]. However, there is limited evidence in relation to the current classification, and thus, the present study was performed to classify the patients of pauci-immune glomerulonephritis according to this new classification and to assess the impact of this on the treatment outcomes. 2 Patients had secondary causes 11 Patients lost to follow up 57 Patients in follow up 86 Patients 84 Patients 73 Patients 16 Expired Materials and methods The present study was an observational study done between July 2006 and October All patients with a renal biopsy diagnosis of pauci-immune glomerulonephritis between July 2006 and July 2010 were included retrospectively and those diagnosed between July 2010 and October 2012 were enrolled prospectively. The subjects details including clinical evaluation and investigations were noted according to the preformed questionnaire. The disease activity was assessed by the Birmingham Vasculitis Activity Score (BVAS), version 3 [15]. ANCA positivity and type were determined by ELISA and indirect immunofluorescence (IIF) method. Hemoglobin, blood urea, serum creatinine, ESR, CRP, hematocrit, urine routine examination and microscopy and 24-h urinary protein at time of biopsy were noted. The patients were followed up with hemogram, blood urea, serum creatinine, urine examination, 24-h urinary protein at first, third and sixth months of treatment. The renal biopsies were reviewed and classified according to the new classification. The patient s treatment regimens were not interfered with and the patients were treated according to the standard protocol decided by the treating unit. The treatment outcomes noted were improvement in renal parameters, deterioration in renal functions and death at the end of 6 months. Normalization of serum creatinine or <30 % rise of serum creatinine from baseline value not requiring renal replacement therapy was considered as improvement in renal functions, while a rise in serum creatinine >30 % from baseline or requirement of maintenance hemodialysis was considered as deterioration in renal function. The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000, and the study was approved by the Institute Ethics Committee. Fig. 1 Flow chart depicting the inclusion of patients A total of 86 patients were included in the study. Out of which 2 patients were excluded from analysis due to the presence of secondary causes for renal dysfunction (acute cortical necrosis and membranous glomerulopathy in one each). Eleven patients were lost to follow-up, and 16 patients died during follow-up period (Fig. 1). Statistical analysis The data of all the subjects were entered in the Microsoft Office Excel sheet and analyzed using Statistical Package for the Social Sciences (SPSS) software (IBM, New York, USA). For descriptive statistics, continuous variables were reported in terms of mean, standard deviation and range, and categorical variables were presented as percentages. For univariate analysis, categorical variables were analyzed using chi-square test; Student s t test or Mann Whitney tests were used for continuous variables. ANOVA was performed for multiple comparisons of means. Logistic regression was used for finding any predictors of outcome from the baseline characteristics. Survival curves were constructed according to the Kaplan Meier method. A p value of <0.05 was considered as statistically significant difference. Results Demographic and clinical data Eighty-six subjects were included in the study, of which 51.2 % were females. The mean age was 42.5 ± (range 14 70) years. The baseline characteristics of the

3 1723 Table 1 Baseline characteristics Parameters (n = 86) N (%) Age (years) 42.5 ± Sex Male 42 (48.84) Female 44 (51.16) ANCA Positive 53 (61.63) Negative 33 (38.37) Diagnosis GPA 34 (39.53) MPA 36 (41.86) CSS 1 (1.16) Unclassified 15 (17.44) Lab parameters Mean (standard error) Hb (g/l) 85.8 (1.97) Urea (mmol/l) 49.8 (2.56) Creatinine (µmol/l) (49.25) egfr (ml/min/1.73 m 2 ) 19.4 (2.33) Albumin (g/l) 31.7 (0.75) 24 h UP (g) 1.9 (0.16) Hematuria (%) 77.9 study population are shown in Table 1. At the time of biopsy, 66 patients (77.74 %) had anemia (Hb < 100 g/l). The mean serum creatinine at presentation was µmol/l (range ,245.3 µmol/l) with mean egfr of ml/min/1.73 m 2 (range ml/ min/1.73 m 2 ), while renal dysfunction was present in 77 patients (89.53 %) at onset. Proteinuria was present in 52 patients (60.47 %), out of which 11 patients had nephrotic range proteinuria (>30 g/l). Urine microscopy showed the presence of active sediments in 67 patients (77.91 %). Thirty-three patients (38.37 %) were ANCA negative. The renal manifestations were present in 82.6 % of the patients at the time of presentation and included pedal edema (75.6 %), facial puffiness (33.7 %), decreased urine output (47.7 %) and anasarca (17.4 %). Other clinical manifestations according to the clinical diagnosis are summarized in Table 2. Intravenous methylprednisolone was given in 53.5 % (n = 46) of patients for induction of remission. Oral steroids were started in 91.9 % (n = 79) of patients at mg/kg/day, which were gradually tapered from third to sixth months. Cyclophosphamide was used as induction therapy in 74.4 % (n = 64) patients, of which 43 patients (50 %) received it intravenously. Plasmapheresis was given in 14 % patients (12), while hemodialysis was given in 50 % (n = 43) of patients. Histopathological classification of renal biopsies All the renal biopsy specimens were re-evaluated and classified according to the new classification. Thirteen patients (15.5 %) were classified as focal, 43 patients (51.2 %) as crescentic, 12 patients (14.3 %) as sclerotic and 16 patients (19 %) as mixed class. Figure 2 shows representative photomicrographs of the four histopathological groups. The distribution of different histological classes according to the clinical diagnosis is shown in Table 2. Clinico pathological correlation The baseline investigations showed a much lower levels of blood urea, serum creatinine and 24-h urinary protein in the focal class as compared to the other 3 classes. Similarly, the baseline hemoglobin and serum albumin were higher in the focal class. However, significant difference was seen only for blood urea (p = 0.018) and hemoglobin (p = 0.04) levels. The various investigations at baseline and at 6-month follow-up among the 4 classes are shown in Table 3. Of the 86 patients included in the study, 16 patients were lost to follow-up at the end of 6 months. In the focal class, % showed improvement in renal functions, and only one patient had worsening of renal parameters requiring hemodialysis. In the crescentic class, 17/35 patients (48.57 %) had improvement in renal parameters, 11 patients (31.42 %) had worsening in renal functions and 7 patients (20 %) expired. Among the 10 patients in the sclerotic class, 5 patients (50 %) expired, 2 patients (20 %) had worsened renal functions and only 3 patients (30 %) had improvement. In the mixed class, 6/13 patients (46.15 %) had improvement, 3 patients (23.08 %) deteriorated and 4 patients (30.76 %) expired. The difference in improvement rates was statistically significant between the focal class versus the other three classes together (p = 0.008). Comparison between individual class showed significant difference between focal and crescentic class (p = 0.022), focal and sclerotic class (p = 0.011), and focal and mixed class (p = 0.045). However, there was no interclass difference between other classes (Table 4). Statistically significant difference in death rate was found only between focal and sclerotic class (p = 0.023). This difference in outcomes between various histological classes was maintained irrespective of their clinical diagnosis, thus implying that the treatment response is affected by the histological class and not the underlying clinical diagnosis. The Kaplan Meier curve for the survival probability is shown in Fig. 3, while Fig. 4 shows the Kaplan Meier curves for probability of development of end-stage renal disease among the four classes.

4 1724 Rheumatol Int (2014) 34: Table 2 Manifestations and histological classes according to clinical diagnosis (%) GPA (n = 34) MPA (n = 36) CSS (n = 1) Unclassified (n = 15) Renal Pulmonary Upper respiratory Gastrointestinal Neurological Musculocutaneous Ocular Constitutional Histopathological class Focal Crescentic Sclerotic Mixed Fig. 2 Representative photomicrographs of the four histopathological classes. a Focal, b crescentic, c sclerotic, d mixed

5 1725 Table 3 Investigations at baseline and 6 months according to histopathological class Variable Mean (SE) Focal Crescentic Sclerotic Mixed Baseline 6 months Baseline 6 months Baseline 6 months Baseline 6 months Hb (g/l) 95.2 (5.2) 99.8 (4.8) 84.0 (2.8) 93.2 (2.6) 76.1 (5.1) (4.3) 88.7 (4.6) 106.9* (4.1) Urea (mmol/l) 30.9 (6.6) 14.1 (5.3) 49.6 (3.6) 27.6 (4.9) 58.1 (6.9) 27.5 (5.7) 58.4 (5.9) 34.1 (4.9) Creatinine (µmol/l) (129.2) (73.3) (69.1) 306.8* (38.7) (126.1) (80.2) (112.6) 225.4* (68.9) egfr (ml/min/1.73 m 2 ) 33.8 (6.0) 54.6* (9.9) 14.8 (3.3) 40.8* (5.3) 15.1 (6.3) 26.4 (10.9) 21.2 (5.4) 54.2* (9.3) Albumin (g/l) 34.5 (2.0) 40.3 (1.7) 30.5 (1.1) 33.6 (1.5) 31.0 (1.9) 30 (1.7) 32.5 (1.8) 38.8 (1.5) 24 h UP (g) 1.3 (0.4) 0.3 (0.2) 2.0 (0.2) 1.4* (0.12) 1.7 (0.4) 2.6 (0.2) 1.5 (0.4) 1.3 (0.15) Hematuria (%) * p < 0.05 Table 4 Treatment outcomes at 6 months Outcome at 6 months Focal* (n = 12) Crescentic (n = 35) Sclerotic (n = 10) Mixed (n = 13) Remission [N (%)] 11 (91.67) 17 (48.57) 3 (30) 6 (46.15) Refractory [N (%)] 1 (8.33) 11 (31.42) 2 (20) 3 (23.08) Died [N (%)] 0 7 (20) 5 (50) 4 (30.76) * p value = 0.008: focal versus others, while p = NS for crescentic versus others, sclerotic versus others and mixed versus others BVAS and survival The mean BVAS score at baseline was (range 8 38). The patients were categorized into 2 groups based on BVAS into <20 and 20 to look at impact of severity of disease. Fifty-three patients had BVAS < 20, and 31 patients had BVAS > 20. Out of those with BVAS < 20, thirty patients (56.60 %) were in crescentic group, 7 (13.21 %) were in focal group, 9 (16.98 %) in sclerotic group and the remaining 7 (13.21 %) were in mixed category. Among patients with BVAS > 20, thirteen patients (40.63 %) had crescentic, 6 patients (18.75 %) had focal, 3 (9.38 %) had sclerotic and 9 (28.13 %) had mixed histology. The distribution of various histological class, treatment outcome or mortality did not differ according to the BVAS score. Discussion In 2010, the international working group of renal pathologists had proposed a classification system based on the glomerular pathology to look for the severity of renal involvement and to determine the prognosis in patients with ANCA-associated glomerulonephritis [2]. Subsequently, there had been a limited data on the utility of this classification, and thus, we conducted this study. Our patients of ANCA-associated glomerulonephritis were younger with the mean age of 42.5 ± 15 years. In another study done from southern India, the mean age of Fig. 3 Kaplan Meier curves showing survival probability according to the histopathological classes (p = for focal versus sclerotic, rest NS) patients was 43.4 years [16]. This is in contrast with studies from other parts of world, where the mean age is in the range of years [2, 17 28]. Thus, it may be possible that AAV affects younger people in our country as compared to western population. However, the distribution of patients according to various clinical classes was

6 1726 Rheumatol Int (2014) 34: Fig. 4 Kaplan Meier curves showing probability for end-stage renal failure (ESRD) among various histological classes. p = 0.04 for focal versus crescentic, rest NS comparable to that reported in other studies. Our study had 15 patients, who were unclassifiable and probably constitute the renal limited vasculitis (RLV). These patients had only renal involvement, while other symptoms such as breathlessness, constitutional symptoms, nausea and vomiting seen in some of them could be explained due to uremia. In our study, % of the patients were ANCA negative, which is higher as compared to other studies [2, 28 34]. This may be because of difference in inclusion criteria. While our study had included patients with histological diagnosis of pauci-immune glomerulonephritis, irrespective of their ANCA status, previous studies have included only those patients who had positive ANCA. Few studies which included the patients with pauci-immune glomerulonephritis have reported ANCA negativity between 9.15 and % [35 37]. Nonetheless, the various clinical manifestations and the frequency of renal and pulmonary involvement were similar to other studies. In a study of 100 European subjects, Berden et al. [2] observed 16, 55, 13 and 16 % subjects in the focal, crescentic, sclerotic and mixed class, respectively, while in the Chinese study, the figures were 27.3, 43.8, 9.1, and 19.8 %, respectively [19]. These figures are comparable to that in our study, depicting crescentic to be the most common histological class. However, in a recently published study from Japan, focal class was reported to be the most common (45.1 %) followed by crescentic class (31.37 %) [28]. In our study, the histopathological class correlated with the initial serum creatinine and proteinuria levels, with much lower levels seen in the focal class as compared to other classes. Similarly, the treatment outcomes at the end of 6 months were better in the focal class with improvement in renal parameters in % of the patients. The worst outcomes were seen in sclerotic group with only 30 % of patients showing improvement in renal functions, with a mortality rate of 50 %. This finding suggests that this classification be used to predict the prognosis of the patients. This difference in outcomes seen among different histological classes was irrespective of the underlying clinical diagnosis, and thus, it may be more useful to classify patients with pauci-immune glomerulonephritis according to the histological class rather than the clinical diagnosis, as it is the histological changes which matters in the outcomes of these patients. In our study, the probability of worsening renal outcome and mortality increased with ascending sequence of focal, crescentic, mixed and sclerotic groups. Similar results were observed by Berden et al. and Iwakiri et al. in their studies; however, Chang et al. observed that the probability of progression to end-stage renal disease (ESRD) increased from focal to mixed to crescentic to sclerotic groups [2, 19, 28]. Thus, we can conclude from our study as well as from available evidence that the best outcomes are seen in the focal class and worst in the sclerotic class. Our study is limited by the small sample size, and also it included patients from a single center, where the patients from particular region predominate. Thus, the results of this study may not be applied to subjects from other region or races. A larger multicentre or multinational study is required to further validate the results of our study. We did not analyze the vascular or tubulo-interstitial changes in our patients and thus cannot comment on their effect on the outcome. Also, the number of patients with ANCA negativity was higher in this study as we included patients with pauci-immune glomerulonephritis irrespective of their ANCA status. Conflict of interest None. References 1. de Lind Van Wijngaarden RA, Hauer HA, Wolterbeek R et al (2006) Clinical and histologic determinants of renal outcome in ANCA-associated vasculitis: a prospective analysis of 100 patients with severe renal involvement. J Am Soc Nephrol 17: Berden AE, Ferrario F, Hagen EC et al (2010) Histopathologic classification of ANCA-associated glomerulonephritis. J Am Soc Nephrol 21: Hogan SL, Nachman PH, Wilkman AS, Jennette JC, Falk RJ, the Glomerular Disease Collaborative Network (1996) Prognostic

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