Introduction
Crescentic glomerulonephritis (CSGN) is a pathological condition that is characterized by involvement of glomeruli extensively (more than 50%) with crescents with or without accompanying glomerular tuft hypercellularity. The clinical hallmark of CSGN is rapidly progressive glomerulonephritis (RPGN). This manifests as progressive deterioration in renal function in days, or weeks or months rather than years.1
It has been reported that CSGN comprises 2-10% of the total number of kidney biopsies.234 The primary diseases that subsequently develop CSGN show regional variation.5 The clinical and epidemiological factors of CSGN and their histopathology and outcome in the Indian population are unclear. There is reported literature of CSGN in children in the region; however, data in adult patients are scarce and hence this study was planned for the same. The purpose of the study was to investigate the incidence, the underlying primary disease, clinical characteristics and their histological features in a population from Eastern India.
Materials and Methods
This is a retrospective observational study. The study was conducted in the Department of Nephrology and Pathology, Institute of Medical Sciences, Banaras Hindu University from January 2008 to June 2011. The biopsy-proven cases of CSGN were included. Only those cases where >50% glomeruli showed crescents were included. Those cases of focal crescents are excluded from the study. Those cases who have insufficient data are also excluded. The details of hospital admission records were analyzed and patients were subsequently followed at the outpatient department.
Definitions used67
Nephrotic-range proteinuria (NS) was defined as proteinuria >3.5 g/day with or without hypoalbuminemia.
Acute nephritic syndrome was defined as hematuria, RBC casts and proteinuria (<3.5 g/ day), which persist <3 months.
RPGN syndrome was defined as acute nephritic syndrome with acute deterioration in renal function, such as a two-fold increase in serum creatinine concentration or a decrease in creatinine clearance by 50%.
Chronic nephritic syndrome/CSGN was defined as proteinuria (1-3.5 g/day) and hematuria that persisted for more than three months.
Remission was defined as the level of serum creatinine <1.4 mg/dL and proteinuria of <0.4 g/day.
Partial remission was defined as serum creatinine decrease 50% if it is more than 2.3 mg/dL and proteinuria decrease 50% than that initially.
Histopathology
All renal biopsy specimens were processed for light microscopy at the histopathology section. Immunoflorescence and electron microscopy were not performed due to non-availability at our institute during the study period. Two pathologists reviewed the histopathologic findings. For light microscopy, renal tissue samples were fixed in 10% formaldehyde, embedded in paraffin and cut into thin sections. Sections were stained with hematoxylin and eosin, periodic acid-Schiff and Masson's trichome. AFOG stain was performed for immune deposits.
Serology
ANA, Anti-Ds DNA antibody, ANCA and Anti-GBM antibodies were measured by ELISA methods using Kits of Phoda Co.
Serum complements
The reference ranges for C3 and C4 were 72-156 mg/dL and 20-50 mg/dL, respectively. ASO titer >200 titer is considered positive.
Statistical Analysis
The data were encoded using Microsoft Excel and analyzed using SPSS Software version 16.0. Descriptive statistics such as mean, standard deviation and proportions were computed for the different variables of interest. For determining relationships and correlation of variables, chi-square test, Fisher's exact test, Pearson's correlation and ANOVA were used in the analysis of appropriate variables. A P-value of less than 0.05 was considered significant.
Results
Incidence of CSGN
There were 37 cases of CSGN, of which three cases were excluded due to insufficient data. The incidence of CSGN was 5.5% out of 670 non-transplant kidney biopsies performed during the period. The male to female ratio was 12:22. The mean age of presentation was 32.44 ± 15.9 (range: 12-72) years. Four (11.7%) patients were between 60 and 72 years and four (11.7%) patients were below 20 years. The clinical presentation and laboratory features are shown in Table 1.
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Table 1: Clinical and laboratory parameters of CSGN patients.
The median time of presentation was 30 days (range: 10-365 days). The remarkable observation was that 20.5% of the patients presented as CRF and 38.2% of them had non-oliguric renal failure at presentation. Serum creatinine at presentation was ≥5.5 mg/dL in 13 (38.2%) patients, >3-5.4 mg/dL in 12 (35.3%) patients and <3 mg/dL in nine (26.4%) patients.
The immunological profile of CSGN is shown in Table 2. The remarkable observations were that four (11.7%) patients were positive for both ANCA and anti-GBM antibodies and two (5.8%) lupus nephritis patients were ANCA positive. One patient had both PR3 and MPO ANCA positivity. Anti-GBM antibody was positive in five (14.7%) patients and lupus nephritis was present in six (17.6%) patients. All the three antibodies were present in one patient. One case of each membranous nephropathy and post-streptococcal glomerulonephritis were associated with CSGN. In 15 (44.1%) cases, it was diagnosed as idiopathic CSGN.
Table 2: Immunopathologic characteristics of CSGN patients.
Three of four double-positive (anti-GBM anti-body and ANCA) patients died, and the remaining patient showed partial remission. Both the patients of lupus nephritis with ANCA positivity were in CRF at last follow-up and showed partial remission (Table 4).
Follow-up data were not available for three patients. The median follow-up time was five months (range: 2-36 months). The outcome of patients is shown in Table 3. The median time for remission was 75 days (range: 25-150 days). The factors associated with worse outcome were dialysis dependency, anti-GBM and/or ANCA positivity and oligoanuria, as shown in Table 4.
Table 3: Outcome and treatment of the CSGN patients.
Table 4: Outcome analysis at the end of the third month from diagnosis.
The causes of death were massive hemoptysis (1), sepsis with pneumonia (2) and intracranial and intramedullary hemorrhage (3). Median time for death was 15 days.
Discussion
This is a retrospective study of 34 patients of CSGN, where the incidence of CSGN was 5.5% of kidney biopsies. The incidence of CSGN varies with geographic location and policies of kidney biopsies. The incidence of CSGN was 1.75% in a study from China.8 However, studies from Western Europe and North America (2-10%) and South Africa (3.8%) showed a near-similar incidence.2345 Gupta et al9 found an incidence of 2.65% of kidney biopsies, but the study included both pediatric and adult patients. The difference with the present study may be due to the differing patient cohorts and policies of kidney biopsies. CSGN occurs in all ages. The mean age of presentation in our study was 32.44 ± 15.9 years, with a predominance of female sex (male to female ratio 0.54). Gupta et al9 from India also observed younger age of presentation of CSGN (27.6 + 17.1 years). However, the study population included 26% of the pediatric group. There was a female predominance in immune complex-mediated CSGN.9 The female predominance is due to the higher prevalence of immune complex diseases.
Thirty percent of the patients of CSGN present with chronic renal failure.8 Although the most common presentation of CSGN was RPGN (67.7%) in the present study, a number of patients of CSGN presented with CRF-CGN (17.6%) and nephrotic syndrome (6.0%). Although statistically not significant, they had better outcome. This is in contrast with the dictum "CSGN is the pathologic entity for clinical syndrome RPGN." These patients had an insidious onset of disease and slowly progressive course that led to late presentation. Health awareness as well as the economic status of our patients may be the contributory factor. Among patients of CRF presentation, 71.4% remained in CRF and 28.6% showed remission, and none progressed to ESRD or had mortality till three months (P-value 0.28). However, patients who presented with RPGN had a higher mortality or ESRD (Table 4). Because of an insidious onset and slow progression, these groups of patients are often diagnosed too late and, by that time, irreversible histopathological changes occur and potential immunosuppressive therapy remains questionable.
While considering the etiology of CSGN, the present study revealed that idiopathic (44.1%) is the most common variety, followed by ANCA-associated (23.5%) and lupus nephritis (11.7%). Vasculitis is the most common form in western countries.234 Data from a study in China demonstrated that lupus nephritis was the most common etiology, followed by IgA nephropathy and vasculitis.8 Progression to ESRD or mortality was lower among patients of unknown etiology than known etiology (statistically not significant). Prospective studies with large number of patients required to substantiate the findings.
Four patients (13.3%) in our study had both Anti-GBM antibodies and were ANCA positive. Three had MPO-ANCA and one patient had PR3-ANCA. They had worse outcome; three of them died and one progressed to CRF (P-value 0.00). Levy et al (2004) reported that 82% of patients (n = 27) of double-positive had MPO-ANCA. Our study revealed 75% MPO-ANCA and 25% PR3-ANCA double-positive patients. The study also demonstrated poor outcome in double-positive patients.10
The overall frequency of ANCA in Goodpasture's disease is 30%,11 whereas patients with ANCA-associated vasculitis develop anti-glomerular basement antibodies in <5% of the cases.12 Usually, both antibodies occur together at the time of clinical presentation. Concomitant ANCA positivity in patients of anti-GBM disease affects the prognosis, whereas some authors describe an unfavorable outcome for those patients with double positivity1213 and others disagree.141516 A study from the Netherlands showed that patient and renal survival is different in double-positive patients (statistically not significant) than positivity of either. Renal survival at one year was 65%, 10% and 15% in ANCA, double-positive and anti-GBM-positive patients, respectively.16 Renal failure was lower in ANCA-positive patients compared with double-positive or anti-GBM-positive patients (5.0, 10.3 and 9.6 mg/dL, respectively; P = 0.01). Levy et al12 analyzed 27 patients with CSGN and double-positivity for anti-GBM antibodies and ANCAs (mostly MPO-ANCA), and described patient and renal survival rates of 52% and 26%, respectively, at one year. Sixty-eight percent of patients were dialysis dependent at presentation, and none of them recovered renal function, despite immunosuppression with or without plasma exchange.
Although patients with CSGN and double-positivity for anti-GBM antibodies and ANCAs may have a poor prognosis when presenting with severe disease, behaving more like anti-GBM disease than vasculitis, recovery from severe renal failure may be rare. They are the candidates for aggressive immunosuppressive therapy with plasma exchange, which can improve renal outcome.
In this study, there was one patient with positive ANA, anti-dsDNA, ANCA and anti-GBM positivity and one patient with ANCA and anti-dsDNA positivity. The former patient showed partial remission and progressed to CRF, while the patient improved later and is presently without dialysis (Table 4). The role of triple positivity is uncertain. Approximately 20% of patients with SLE have ANCA positivity by immunoflorescence, mainly with a p-ANCA pattern.17 A study on 566 patients with SLE from multiple centers in Europe found ANCA positivity by immunoflorescence in 16.4% of patients, including 15.4% p-ANCA and 1% c-ANCA.18 Histologically, they are characterized by prominent necrosis and crescent formation in the absence of significant endocapillary proliferation or subendothelial deposits.1920 It has been suggested that abnormalities in both humoral and cell-mediated immunity are involved in lupus nephritis patients positive for MPO-ANCA.21 These cases represent the coexistence of LN with ANCA-associated necrotizing and crescentic GN. In the setting of LN with ANCA-associated GN, aggressive immunosuppressive therapy is warranted.22 The precise role of ANCA in the pathologic course of crescentic lupus nephritis remains unclear.23 Another patient had both PR3 and MPO-ANCA positive. The clinical significance of both types of ANCA positivity in the same patient is uncertain. The patient was a middle aged female who has shown improvement with cytotoxic regimen. There are case reports of sequential presence of both MPO and PR3 ANCA in the same patient.24
The present study revealed that fibrocellular crescents were the most common type of crescents, followed by cellular crescents. The higher prevalence of fibrocellular (65%) crescents and interstitial fibrosis (20.5%) portend to poor outcome of CSGN in the study.
The present study revealed a mortality rate of 9.9% among patients of CSGN. The median time of death was 15 days. The mortality within the first year was 13.9% in a study by Mark et al (2004) in patients of small vessel vasculitis.25 Marjan et al reported a mortality of 20% within the first year of diagnosis.26 The present study accounted for a mortality up to three months after diagnosis, and three (9%) patients had no follow-up data that may explain low mortality. Further, prolonged follow-up is necessary to document mortality outcome. Follow-up at three months revealed a remission rate of 23.5%. There is no uniform definition of remissions in CSGN. Again, remission differs among the type of etiology of CSGN. The remission rate is lowest in anti-GBM disease. It is demanded that the remission rate be 80-90% among patients of CSGN. A comparative low rate of remission in this study is an audit of presentation at advanced renal failure, slowly progresssive disease in few patients, low socio-economic status and poor education.
Limitations of the Study
- Retrospective study
- Lack of immunoflorescence
- Lack of long-term follow-up
- Small number of patients in the study.
Conclusion
CSGN carries poor prognosis. Majority of our patients reported in advanced stages of renal failure, which has a strong bearing on outcome. CSGN can have an insidious and slowly progressive course. Early recognition and timely intervention are required to prevent progression to CRF or ESRD. Anti-dsDNA, anti-GBM antibody and ANCA can coexist in CSGN.
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