| Abstract|| |
Background: Crescentic glomerulonephritis (CrGN), defined as crescents involving more than 50% of the glomeruli, includes pauci-immune, immune complex-mediated and anti-glomerular basement membrane disease. Objectives: The present study was aimed at evaluating the various clinical, biochemical and histological parameters in CrGN with respect to these categories and clinical outcome. Materials and Methods: Renal biopsies diagnosed as CrGN between Jan 2008 and Feb 2010 were included. Clinical and laboratory parameters were retrieved along with the therapeutic approach and clinical outcome, wherever available. Renal biopsy slides were evaluated for various glomerular, tubulo-interstitial and arteriolar features. Appropriate statistical tests were applied for significance. Results: A total of 46 cases of CrGN were included; majority (71.7%) of cases were pauci-immune (PI) while 28.3% were immune complex-mediated (IC). Among clinical features, gender ratio was significantly different between PI and IC groups (P = 0.006). The various histological parameters, including proportion of cellular crescents, tuft necrosis and Bowman's capsule rupture, were similar in both the groups. Four unusual associations, including idiopathic membranoproliferative glomerulonephritis (MPGN), multibacillary leprosy, acute lymphoblastic leukemia and C1q nephropathy were detected. Adequate follow-up information was available in 21 (46%) of the patients. Of these, 11 (52.4%) were dialysis-dependent at the last follow-up. Adult patients required renal replacement therapy more frequently than pediatric cases (P = 0.05). Presence of arteriolar fibrinoid necrosis also showed association with poor clinical outcome (P = 0.05). Conclusions: Crescentic glomerulonephritis remains one of the main causes of acute renal failure with histological diagnosis. Immunohistologic examination is essential for accurate classification into one of the three categories. This condition should be considered in rare causal associations like leprosy or MPGN with renal failure, to allow for timely performed renal biopsy and appropriate aggressive therapy.
Keywords: Crescentic glomerulonephritis, immune complex-mediated, outcome, pauci-immune
|How to cite this article:|
Gupta R, Singh L, Sharma A, Bagga A, Agarwal SK, Dinda AK. Crescentic glomerulonephritis: A clinical and histomorphological analysis of 46 cases. Indian J Pathol Microbiol 2011;54:497-500
|How to cite this URL:|
Gupta R, Singh L, Sharma A, Bagga A, Agarwal SK, Dinda AK. Crescentic glomerulonephritis: A clinical and histomorphological analysis of 46 cases. Indian J Pathol Microbiol [serial online] 2011 [cited 2019 May 19];54:497-500. Available from: http://www.ijpmonline.org/text.asp?2011/54/3/497/85081
| Introduction|| |
Crescentic glomerulonephritis (CrGN) constitutes one of the leading histopathologically diagnosed etiologies of acute or rapidly progressive renal failure. As an entity, CrGN has been reported to be uncommon in children.  On immunohistologic examination, CrGN has been classified as pauci-immune, immune complex-mediated and anti-glomerular basement membrane disease, of which pauci-immune cases account for majority of CrGN.  Few earlier studies have evaluated the clinico-pathologic distinction between pauci-immune and immune complex-mediated CrGN. These studies have demonstrated higher proportion of crescents in pauci-immune cases with frequent necrosis in ANCA-associated and lupus CrGN.  Evaluation of features for predictive value in earlier studies has shown a correlation of activity of crescents and tubulo-interstitial chronicity with clinical outcome.  However, there is a paucity of data on clinico-pathologic correlates of CrGN from developing countries.
The present study was aimed at evaluating the various clinico-pathologic features in cases of crescentic glomerulonephritis with an attempt at correlating these features with immunofluorescence findings and the clinical outcome.
| Materials and Methods|| |
This study included patients diagnosed as crescentic glomerulonephritis (CrGN) over a two-year period (Jan 2008-Feb2010). CrGN was defined as presence of epithelial crescents filling the Bowman's space in ≥50% glomeruli in the renal biopsy.
Detailed clinical and biochemical evaluation was done for these patients. Clinical details included age, gender, duration of presenting complaints, presence of hypertension, duration of follow-up, therapeutic regime given and clinical outcome with regards to renal function (serum creatinine). Biochemical parameters, including serum creatinine at diagnosis and at last follow-up, urine routine and microscopic examination, including 24-hour urinary protein level were recorded. Serological investigations for anti-nuclear antibody (ANA), anti- neutrophil cytoplasmic antibody (ANCA), anti-double stranded DNA (dsDNA) and serum complement levels (C3) were also recorded.
All the patients underwent renal biopsy, which were evaluated by three independent pathologists (RG, AS, AKD) who were blinded to the clinical outcome. For light microscopy, routine tissue processing was performed with hematoxylin-and-eosin, periodic acid Schiff and silver methenamine stains. Histological features, including total number of glomeruli, number (and proportion) of glomeruli with crescents, number (and proportion) with cellular/fibrocellular/fibrous crescents, presence of tuft necrosis, presence of rupture of Bowman's capsule, degree of interstitial fibrosis and tubular atrophy, arteriolar fibrin deposition and presence of arteriolar fibrinoid necrosis were recorded for all the biopsies.
Immunofluorescence staining for IgA, IgG, IgM, C3, C1q and fibrinogen was performed on frozen sections of renal biopsy in all the cases. The positivity, pattern and intensity (semi-quantitative scoring) of staining were recorded.
Student's t-test was applied for normally distributed data while Mann-Whitney U-test was used for numerical data with non-normal distribution. Chi-square test was utilized for categorical variables. A P value of <0.05 was considered as significant.
| Results|| |
A total of 1742 native kidney biopsies were received in our department during the study period. Of these, 46 (2.65%) were diagnosed as CrGN.
The mean age of patients was 27.6 years (±17.1 years, range 4.5-72 years). Of the 46 patients, 12 (26.08%) were in the pediatric age group (<14 years of age). There were 22 males and 24 females (male: female 0.9: 1). The etiology of CrGN was immune complex-mediated (IC) in 13 (28.3%) and pauci-immune (PI) in 33 cases (71.7%). Comparing the groups of IC and PI, the mean age and proportion of pediatric patients were similar. However, the gender ratio was significantly different. In the PI group, male: female ratio was 1.5: 1 while a striking female preponderance was noted in the IC group (male: female 2: 11, P value 0.006). The duration of symptoms, presence of hypertension at renal biopsy and median serum creatinine were similar in both the groups. Of the patients with PI CrGN, 15 (45.5%) showed positive serology for anti-neutrophil cytoplasmic antibody (ANCA). Among the IC patients, 11 had features of systemic lupus erythematosus (SLE). The relevant clinical and biochemical characteristics are summarized in [Table 1].
|Table 1: Summary of clinical and biochemical features of 46 cases of crescentic glomerulonephritis|
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The median number of glomeruli was 13 (range 8-53) in PI group and 10 (8-30) in IC group. A median of 13.3% and 14.3% glomeruli showed global sclerosis in PI and IC group, respectively. The proportion of glomeruli displaying cellular crescents was 21.7% (0-100%) in PI and 34.8% (0-77.8%) in IC-mediated CrGN, with no significant difference between the two groups. Five cases in PI group showed prominent fibrous crescents involving >50% of the glomeruli. The presence of tuft necrosis, Bowman's capsule rupture and fibrinoid necrosis of arteriolar wall was similar in both groups (P value >0.05). The degree of tubular atrophy and interstitial fibrosis was comparable in both the groups. The salient histological features in the two groups are tabulated in [Table 2] and depicted in [Figure 1] and [Figure 2].
|Figure 1: Photomicrographs from a case of lupus CrGN (a) showing circumferential cellular crescent with tuft necrosis and hemorrhage within the crescent (H and E, x200). (b) Immunofl uoroscence staining for C1q shows granular capillary wall deposits (FITC, x200). A case of pauci-immune CrGN (c) shows cellular to fibrocellular crescents (H and E, x100) (d) showing fi brin deposition in the arteriolar wall (H and E, x400)|
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|Figure 2: Renal biopsy (a) showing predominantly fi brous crescents (H and E, x100) (b) focal interstitial chronic inflammation (H and E, x200). (c) Signifi cant tubulo-interstitial fibrosis seen in a case of pauciimmune CrGN (H and E, x40) (d) with cellular to fi brocellular crescents (H and E, x200)|
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|Table 2: Histopathological evaluation of 46 cases of crescentic glomerulonephritis|
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On immunofluorescence staining, 33 cases showed little or no staining for IgM and were classified as PI CrGN. Eleven (11) biopsies showed 'full-house' pattern of capillary wall granular staining for IgA, IgG, IgM, C3, C1q and fibrinogen. These were diagnosed as lupus nephritis, on the basis of clinical and serological evidence of SLE. One biopsy showed capillary wall granular deposit of IgG, IgM and C3 with thickening and splitting of peripheral glomerular basement membrane; this case had been diagnosed as membranoproliferative GN five months earlier. Another patient had dominant C1q mesangial deposits along with IgM staining on immunofluorescence with absence of IgA, IgG and C3. This case was interpreted as C1q nephropathy with CrGN.
Detailed clinical follow-up information (mean duration of follow-up six months) was available in 21 patients. Of these, three required dialysis while two were given plasmapheresis. Sixteen patients received steroid pulse therapy and eight of these also received cyclophosphamide and/or azathioprine.
At the last follow-up, 11 of 21 patients (52.4%) were dialysis-dependent. Among the two groups, 7 of 16 (43.75%) patients in PI and 3 of 5 (60%) in the IC group were dialysis-dependent. Considering the age groups, 3 of 11 (27.3%) pediatric patients required renal replacement therapy compared to 7 of 10 (70%) of adult cases, with a P value of 0.05, Chi-square test.
Correlation of renal outcome was attempted with various clinical, biochemical and histopathological features. Arteriolar fibrinoid necrosis showed a weak association with poor renal outcome (P value 0.05, Mann-Whitney test). Parameters like hypertension, initial serum creatinine, proportion of cellular crescents, presence of tuft necrosis and Bowman's capsule rupture did not correlate with the outcome.
Few unusual associations were found in our study. One patient with pauci-immune CrGN was being treated for multibacillary leprosy and was diagnosed as diffuse proliferative exudative GN on renal biopsy. Over the next two weeks, he had rapid deterioration of renal functions and a repeat kidney biopsy showed CrGN. Another patient, a middle-aged female, was on immunosuppressive therapy for MPGN. She presented with RPRF soon after the immunosuppressive regime was tapered and was diagnosed as IC-mediated CrGN. An adult male with acute lymphoblastic leukemia presented with RPRF three days after completion of induction phase of chemotherapy. A renal biopsy showed ANCA-positive pauci-immune necrotizing CrGN in this patient. Finally, an adult male presented with RPRF and progressive anemia. He showed necrotizing CrGN with strong dominant mesangial deposits of C1q and was diagnosed as C1q nephropathy.
| Discussion|| |
Crescentic glomerulonephritis (CrGN) is one of the most important pathologic correlate of rapidly progressive renal failure. Immunohistologically, CrGN is classified into immune complex-mediated (granular glomerular staining on immunofluorescence), anti-GBM disease (linear IgG staining) and pauci-immune CrGN (little or no staining for immunoglobulins or complement).  Various studies have shown that majority of the cases of CrGN are pauci-immune, with circulating ANCA in >80% of these. ,, Reports from China and Macedonia have shown a relatively higher incidence of IC-mediated CrGN. , This has been attributed to the high prevalence of infection with nephritogenic strains in these regions. In the present study, PI was the most common group (71.7% of cases) followed by IC-mediated CrGN (28.3%). There was no case of anti-GBM disease in our study, probably due to the rarity of this disease.
CrGN occurs at all ages, though IC-mediated CrGN is commoner in younger patients, possibly due to the high incidence of IC-mediated glomerulonephritis in this age group.  Overall, CrGN is uncommon in children. In a study from University of North Carolina Nephropathology Laboratory, patients less than 20 years constituted 11.5% of all cases of CrGN.  In the present study, pediatric patients (<14 years of age) constituted 26% of all cases. Hence, CrGN is an important cause of RPRF in pediatric population as well and this etiology needs to be accurately diagnosed at an early stage.
Few studies have evaluated the clinicopathologic differences between PI and IC-mediated CrGN. A study by Jennette JC showed a younger age group in IC-mediated CrGN but similar gender ratio and serum creatinine.  In the present study, a striking female preponderance was found in the IC-mediated group (P value 0.006), in contrast to the earlier reports. This may be due to the fact that majority of patients in the IC-mediated group were lupus nephritis, a disease with female predominance. The age group, mean duration of illness and serum creatinine at presentation were similar, in concurrence with earlier study. 
Among the histopathological features, the proportion of crescents has been reported to be higher in PI CrGN. In his study, Jennette JC showed that about 90% of patients had crescents with approximately half of the cases showing crescents in ≥50% of glomeruli. On the other hand, ≥50% glomerular crescents were less frequently seen in the IC-mediated group.  Glomerular necrosis was more frequent in ANCA-associated CrGN and lupus nephritis.  The present study included only patients with ≥50% glomerular crescents (as a standard defining feature of CrGN). The average proportion of glomeruli showing crescents was similar in both PI and IC-mediated groups (78.69 ± 15.9% and 72.9 ± 20.9%, respectively). The proportion of cellular crescents was also similar in both the groups of CrGN. The frequencies of tuft necrosis, rupture of Bowman's capsule and arteriolar fibrinoid necrosis were comparable in the two groups (P value >0.05 for all). Hence, no significant difference was found in the histological features between the PI and IC CrGN.
CrGN needs to be managed aggressively with high-dose corticosteroids and cytotoxic drugs. Plasmapheresis is indicated for anti-GBM disease and ANCA-associated GN with pulmonary hemorrhage. ,, Studies have shown that the severity of renal insufficiency before initiation of treatment is a strong predictor of renal outcome. ,, Pathologic severity in terms of activity of crescents and chronicity of glomerular and tubulo-interstitial disease also correlates with prognosis.  A study of CrGN in pediatric patients concluded that large crescents, Bowman's capsule rupture and evidence of chronic histologic changes were helpful prognostic indicators.  Another recent study in pediatric population showed poor outcome with stage 4-5 chronic kidney disease in 59% of patients. In this study, IC CrGN constituted the major fraction of cases (86.3%), with the most common etiology being MPGN.  Srivastava et al. reported progression of renal failure in 53% of their pediatric patients.  In the present study, however, IC CrGN constituted only 25% of the pediatric cases. Progression to chronic kidney disease was seen in 27.3% of pediatric patients, much lower than the previously reported data. Overall, 52.4% of patients (in whom follow-up data was available) were dialysis-dependent in our study. The reason for the difference from previously reported series is not very clear, though it could partly be attributed to the variable inclusion criteria with respect to the proportion of glomerular crescents. Among the various parameters studied, only the presence of arteriolar fibrinoid necrosis had association with renal outcome. None of the other clinical, biochemical or histological features correlated with the outcome.
The present study remarkably puts forth certain unusual associations with CrGN, like multibacillary leprosy, acute lymphoblastic leukemia (with ANCA-positivity), C1q nephropathy and idiopathic MPGN. These cases highlight the need for considering CrGN as a cause of RPRF in such patients and to perform an early renal biopsy for accurate diagnosis and appropriate therapeutic decisions.
In conclusion, crescentic glomerulonephritis is one of the important causes of acute renal failure. Immunofluorescence examination is mandatory to differentiate between the various groups. Though further studies are required, histological features do not appear to provide important prognostic information in cases of crescentic glomerulonephritis.
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Amit K Dinda
Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2]