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Abstract
Lupus nephritis (LN) is one of the most serious systemic lupus erythematosus complications since it is the major predictor of poor prognosis. We present the clinico-histomorphologic characteristics of LN at a center in Dhaka. The study group comprised diagnosed cases of LN on core-needle renal biopsy specimens received in the Department of Histopathology, Armed Forces Institute of Pathology, Dhaka, from January 2018 to June 2019. Histological evaluation and direct immunofluorescence (DIF) study was carried out on each specimen. Each case was classified according to the International Society for Nephrology/Renal Pathology Society (ISN/RPS) Classification 2003 of LN. A total of 104 (9.20%) LN cases were included of total 1130 nonneoplastic renal biopsy specimens. The mean age was 28.29 ± 12.24 years, with a male:female ratio of 1:4.47. According to the ISN/RPS 2003 classification, most of the LN belong to class IV (42, 40.38%), followed by class III (27, 25.96%), class II (22, 21.15%), and so on. The mean age of class IV LN was 25.95 ± 10.15 years, with M:F = 1:4.25. The mean urinary total protein (UTP) was 4.62 ± 4.47 g/24 h and the mean serum creatinine was 1.87 ± 1.12 mg/dL. On histopathology, 22 (52.38%) had crescent formation, 27 (64.28%) had wire loop formation with subendothelial thrombi, and 30 (71.42%) had necrotizing lesion. Interstitial fibrosis and tubular atrophy (IFTA) was ≥25% in eight (19.04%) class IV LN. Among the subclasses, most common was IV-G (A/C) − 16 (38.09%), followed by IV-S (A/C) − nine (21.42%) and IV-S (A) and IV-G (A) each eight (19.04%). In four (9.52%) cases, class IV + V lesion was found. The mean age of class III LN was 26 ± 11.02 years, with a male:female of 1:26. The mean UTP was 3.45 ± 2.4 and serum creatinine was 1.71 ± 1.51. Among these, crescent was found in eight (29.63%) cases, wire loop and subendothelial thrombi in 11 (37.04%) cases, and necrotizing lesions in eight (29.63%) cases. IFTA was >25% in 14.81% of cases of class III LN. Among 27 class III LN, 17 (62.96%) were classified as III (A) and 10 (37.04%) as III (A/C). Two class III LN had an association with class V and two have presented with TMA. The mean age of class II LN was 29.95+ 12.26 years, with M:F = 1:2.66. UTP was 3.53 ± 2.43 g/24 h and serum creatinine was 1.52 ± 1.5 mg/dL for class II LN.
Histologically, these cases had focal/diffuse mesangial proliferation with 25% IFTA in 9.09% of cases. One of the class II LN had associated amyloidosis. Among class V LN, the mean age was 45.12 + 13.64 years, with M:F = 1:3. The mean UTP was 4.06 ± 1.71 g/24 h and serum creatinine was 1.64 ± 0.94 mg/dL. Histologically, 37.5% had >25% IFTA. The mean age of class I lesion was 27.25 ± 17.42 years with equal number of males and females. The mean serum creatinine level was 0.65 ± 0.18 mg/dL and UTP was 2.71 ± 2.3 g/24 h for class I lesion. Only one class VI LN case was found which had IFTA 40% and presented with generalized edema. On DIF, among 100 cases, 86 were found with full-house immune deposits of different intensity; IgM was lacking in 10 cases and IgA was lacking in seven cases, while three cases lacked C3 deposits. The mean activity index was 7.10 and the mean chronicity index was 3.23 among 69 cases of proliferative LN. Among different histological classes of LN, the prevalence of class IV was more in this study which had the most severe form of clinical presentation, biochemical parameters (raised serum creatinine level), and histological findings (crescent formation and IFTA).
Introduction 
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown etiology, in which diverse immunological events can lead to a similar clinical picture, characterized by a wide range of clinical manifestations and target organs (phenotypes) with unpredictable flares and remissions that eventually lead to injury to various organ systems. Renal involvement is a common complication of SLE which is associated with significant morbidity and mortality. Socio demographic factors such as sex, race, and ethnicity play an important role in the incidence of the disease, frequency of its manifestations, and therapeutic response. The renal manifestation is called as lupus nephritis (LN).[1] In SLE patients who have abnormal urine and/or renal dysfunction, renal biopsy is performed to provide prognostic data and direct the initial therapeutic approach.[2]
LN is a classic example of immune complex-induced microvascular injury, which results from circulating double-stranded DNA with anti-DNA antibody complexes and other mechanisms including in situ reactivity for free antibodies with fixed antigens and the presence of sensitized T-cells.[3] Monocyte and neutrophils are accumulated, monocyte chemo-attractant protein type 1, interleukin 1 (IL-1), IL-2 receptors, IL-6, interferons-γ and α, tumor necrosis factor-γ, and transforming growth factor-β are upregulated resulting in chronic inflammation and chronic oxidative damage with clinical manifestations of the disease.[1]
The present classification of LN was published in 2004 jointly by the International Society of Nephrology (ISN) and Renal Pathology Society (RPS). According to this classification, LN is classified as Class I (minimal mesangial LN), Class II (mesangial proliferative GN), Class III (focal proliferative LN), and Class IV (diffuse proliferative LN). In Class IV-S, >50% of involved glomeruli have segmental lesion, while in IV-G, >50% glomerular tuft have a global lesion. In Class V LN (membranous LN), continuous subepithelial deposits with or without mesangial alteration are seen. Class VI is advanced sclerosing GN, and it is diagnosed when ≥90% of glomeruli show global glomerulosclerosis.[4]
About 50%-60% of SLE patients develop the renal disease during their course and 25%|−50% of patients of SLE have the clinical renal disease at onset.[5] Asian SLE patients exhibit higher rates of renal involvement when compared with Caucasians (50−60 vs. 303−8%) and also often lead to a more severe renal disease.[6],[7],[8] In Bangladesh, there is a scarcity of data regarding LN in the literature. A few studies are found in the literature with small cohort. Ul Azim et al have reported renal involvement among 82% of his cohort of 28 SLE patients from the southwestern part of Bangladesh.[9] This study was carried out to find out the histomorphological patterns of LN and their clinical correlation.
Methodology The study group comprised all biopsied renal core-needle biopsy specimens of known SLE patients having clinical evidence of renal involvement, received in the Department of Histopathology, Armed Forces Institute of Pathology (AFIP), Dhaka, from January 2018 to June 2019. A prospective, cross-sectional observational study was carried out during the 18-month duration. Renal involvement was defined by newly developed proteinuria, hematuria, and/or increased serum creatinine level. Histological evaluation of each case was done using standard histological techniques for renal biopsy. Kidney biopsies were processed for light and immunofluorescence microscopy in all specimens, without electron microscopy study, by two pathologists. All data related to the final diagnosis, age, gender, and clinical information were recorded. Each case was classified according to the ISN/RPS classification 2003 of LN. For light microscopy, hematoxylin and eosin, periodic acid−Schiff, Masson trichrome, and Jones methenamine silver stains were used. For direct immunofluorescence (DIF) study, IgG, IgA, IgM, C3, C1q, kappa, and lambda antibodies were used.
Inadequate renal biopsy specimens and biopsy from renal transplant kidneys were excluded from the study. Data were analyzed using the IBM SPSS Statistics version 20.0 (IBM Corp., Armonk, NY, USA). Categorical values were expressed as absolute frequencies and percentages.
Results Excluding one case due to inadequacy, a total 104 (9.20%) cases were diagnosed with LN among a total of 1130 nonneoplastic renal biopsy specimens received during the stipulated time at AFIP, Dhaka, and were included in the study. Among the LN cases, the mean age was 28.29 ± 12.24 years, with 19 males and 85 females (1:4.47). The age distribution is depicted in [Figure 1]; 41.34% was from 21 to 30 years group, followed by 29.8% from <20 years group.
The most common indication for renal biopsy was proteinuria in 99 (95.19%) cases, followed by hematuria in 59 (56.73%) cases and renal impairment (increased serum creatinine) in 45 (43.27%) cases. Among all the cases, 34 (32.69%) had nephrotic-range proteinuria and 30 (28.84%) had nephritic presentation. Others presented with isolated proteinuria or hematuria or renal dysfunction. Demographic, clinical, and biochemical features are shown in [Table 1].
Table 1. Demographic, clinical, and laboratory characteristics of patients (n=104).According to the ISN/RPS 2003 classification,most of the LN belong to class IV (42, 40.38%), followed by class III (27, 25.96%), class II (22, 21.15%), class V (8, 7.69%), class I (4, 3.81%), and class VI (1, 0.96%) [Figure 2].
Figure 2. Lupus nephritis Renal Pathology Society/International Society of Nephrology classes (n=104).The mean age of class IV LN was 25.95 + 10.15 years, with M:F = 1:4.25. The common presentation of class IV was nephritic presentation in 21 (50%) and 20 (47.61%) cases had nephrotic-range proteinuria. The mean urinary total (UTP) was 4.62 ± 4.47 g/24 h and the mean serum creatinine was 1.87 ± 1.12 mg/dL. On histo-pathology, 22 (52.38%) had crescent formation, of which six (14.28%) involved >50% glomeruli (crescentic LN), 27 (64.28%) had wire loop formation with subendothelial thrombi, and 30 (71.42%) had necrotizing lesions. Interstitial fibrosis and tubular atrophy (IFTA) was ≥25% in eight (19.04%) class IV LN. Among the class IV LN, IV-S (A) was eight (19.04%), IV-G (A) was eight (19.04%), IV-S (A/C) was nine (21.42%), IV-G (A/C) was 16 (38.09%), and IV-S (C) was eight (2.38%) [Figure 3]. In four (9.52%) cases, there was an association of class V lesions with class IV.
Figure 3. Renal Pathology Society/International Society of Nephrology Class IV lupus nephritis with microscopic active changes. (a) Endocapillary proliferation with lobular accentuation, (b) Wire loop changes, (c) Cellular crescent formation, (d) Subendothelial thrombi and necrotizing lesion.In class III LN, the mean age was 26 + 11.02 years, with only one male among total 27 cases. In these cases, six (22.22%) presented with nephritic presentation, 10 (37.03%) had [Figure 3]. Renal Pathology Society/International Society of Nephrology Class IV lupus nephritis with microscopic active changes. (a) Endocapillary proliferation with lobular accentuation, (b) Wire loop changes, (c) Cellular crescent formation, (d) Subendothelial thrombi and necrotizing lesion.nephrotic-range proteinuria, and nine (33.33%) had isolated proteinuria. The mean UTP was 3.45 ± 2.4 and serum creatinine was 1.71 ± 1.51 in class III LN. Among class III LN cases, crescent formation was observed in eight (29.63%) cases, wire loop and subendothelial thrombi in 11 (37.04%) cases, and necrotizing lesions in 8 (29.63%) cases. IFTA was >25% in 14.81% of cases of class III LN. Among 27 class III LN, 17 (62.96%) were classified as III (A) and 10 (37.04%) as classified as III (A/C) [Figure 4]. Two class III LN had an association with class V and two have presented with TMA.
Figure 4. Renal Pathology Society/Intemational Society of Nephrology class III lupus nephritis with TMA. (a) Segmental endocapillary proliferation, (b) Glomerular and vascular changes in TMA.The mean age of class II LN was 29.95 + 12.26 years, with M:F = 1:2.66. UTP was 3.53 ± 2.43 g/24 h and serum creatinine was 1.52 ± 1.5 mg/dL for class II LN. The most common presentation is isolated proteinuria in 10 (45.45%) cases, nephrotic-range proteinuria in 10 (45.45%) cases, and hematuria in four (18.18%) cases. Histologically, these cases had focal/diffuse mesangial proliferation with 25% IFTA in 9.09% of cases. One of the class II LN had associated amyloidosis [Figure 5]. Among class V LN, the mean age was 45.12 + 13.64 years, with M: F = 1:3. Nephrotic syndrome was the presentation of 05 (62.5%). In these cases, the mean UTP was 4.06 ±1.71 g/24 h and serum creatinine was 1.64 ± 0.94 mg/dL. Histologically, all had spikes and crater formation in silver staining and 37.5% had >25% IFTA among class V LN.
Figure 5. Renal amyloidosis along with lupus nephritis. (a) Hyaline mesangial deposits. (b) The deposits are PAS positive. (c) Apple green birefringence on Congo red. (d) Monoclonal Lambda deposits on DIF.The mean age of class I lesion was 27.25 ± 17.42 years, with equal number of males and females. All these cases presented with mild proteinuria. Serum creatinine level was 0.65 ± 0.18 mg/dL and UTP was 2.71 + 2.3 g/24 h for class I lesion. Only one class VI LN case was found in our study, which had IFTA of 40% and presented with generalized edema. Demographic, clinical, and laboratory characteristics of different classes are shown in [Table 2].
Table 2. Demographic, clinical, laboratory characteristics of different classes of lupus nephritis (n=104).On DIF study, four cases could not be evaluated due to a lack of glomerulus. Among the rest 100 cases, 86 cases were found with full-house immune deposits of different intensities. Among others, IgM was lacking in 10 cases and IgA lacking was in seven cases, while three cases lacked C3 deposits. The mean activity index (AI) was 4.59 ± 2.06 in class III LN and 8.71 ± 3.41 in class IV LN. The mean chronicity index (CI) was 2.74 ± 1.31 3.23 in class III LN and 3.54 ± 1.58 in class IV LN. Histological characteristics of different classes are shown in [Table 3].
Table 3. Histologic characteristics of different classes of lupus nephritis (n=104). Discussion The renal biopsy in SLE patients performed therapeutic and prognostic purpose. The renal complication in SLE is very common.[10] This study was carried out to evaluate the clinico-histological characteristics of LN. The mean age of LN cases in our study was 28.29 ± 12.24 years, with a male:female ratio of 1:4.47. Biswas et al in Chittagong area found the mean age of 28.42 years with all the female patients, while Baqui et al in their study found the mean age of 26 ± 11.97 years, with a male:female ratio of 1:10.33.[11],[12] In Saudi Arabia, Gomaa et al found mean age 24 h, with a male-female ratio of 1:5.72, and in India, Sharma et al found male-female ratio as 1:8.7 with predominant age group 20−40 years.[13],[14] Farah et al in Jordan found the mean age of LN 29.95 ± 12.16 years, with a male: female ratio of 1:6.[15]
In this study, the nephrotic range of proteinuria was observed in 32.69% and nephritic presentation was seen in 28.84% of cases. While Singh et al reported nephrotic-range proteinuria in 59.62% of cases in a study in Uttar Pradesh, India; in contrast, Devadass et al reported nephrotic-range proteinuria in 23.9% of cases in a study in South India.[10],[16] Hematuria was found in 56.19% of cases in this study. Gomaa et al. reported hematuria in 88.6% of cases of LN, while Sharma et al reported microscopic hematuria in 78.4% of cases.[13],[14] In this study, 59.61% of cases had low serum C3 level, while Farah et al reported low C3 concentration in 75% of cases.[15]
In this study, according to the ISN/RPS 2003 classification, most of the LN belong to class IV (42, 40.38%), followed by class III (27, 25.96%), class II (22, 21.15%), class V (8, 7.69%), class I (4, 3.81%), and class VI (1,0.96%). Studies carried out in India, Nepal, Saudi Arabia, Jordan as well Bangladesh also found LN-Class IV as the predominant histological class of LN, ranging from 40% to 76%.[10],[11],[12],[13],[14],[15],[16],[17] However, one study in East Nepal found class II as the predominant type.[18]
Among the different ISN/RPS classes, there were no significant differences in the mean age of the patients ranging from 25.95 years to 29.95 years during the diagnosis except class IV and class VI. In this study, the mean age in class V was quite higher (45.12 years) and for class VI, it was in a lower range, that is 18 years, though there was only one patient in class VI. Gomaa et al have not found a significant difference in median age among different classes of LN in their series. In their series, the median age of LN class V was 22.5 years and LN class VI was 23 years. In their series, they found the male:female ratio ranged from 1:1.66 to 1:18 in different classes,[13] while in our series, the male:female ratio ranged from 1:1 to 1:27 in different classes of LN.
Among different classes of LN, the mean serum creatinine level and mean UTP were highest in class IV LN in our series. However, except in class I LN, in all the classes, UTP was >3 g/25 h and serum creatinine was >1.5 mg/dL. Nasri et al also found higher mean serum creatinine level in class IV LN, but there was no significant between class III and class IV in mean UTP level.[19] Farah et al so found a similar association of UTP and renal dysfunction with different classes of LN.[15]
In this study, among the subcategory of Class IV LN, the IV-G lesion supersedes IV-S lesion. Among them, the predominant subtype was IV-G (A/C) in 38.09%, followed by IV-S (A/C) in 21.42% of cases and equal distribution of IV-S (A) and IV-G (A) in 19.04% of cases. There was no IV-G (C) lesion in our series; however, only one case had IV-S (C) lesion. Gomaa et al also found IV-G (A/C) as the predominant subtype. However, they have reported 10.8% IV-G (C) lesion, which was lacking in our study.[13] While Devadass et al found IV-G (A) as the predominant (47.05%) subtype in their study.[16]
Among the LN cases, crescent formation was found in proliferative lesions. In our study, crescent formation was found in 52.38% of class IV LN, of which 14.28% were crescentic LN, and in class III LN, 29.63% had crescent formation. Among the proliferative lesions, wire loop formation was seen in 64.28% and 37.04% in class IV and III lesions, respectively. Singh et al in their study reported crescentic LN in 10 out of 28 (35.71%) class IV LN.[10] Another study from China reported crescentic LN among 10% of cases of class IV LN.[20] Nasri et al. reported crescent formation in 42.86% of cases of class III and IV LN,[19] while Zoshima et al reported wire loop lesion in 36% of cases among class III and class IV LN.[21] There was no significant difference in IFTA among class III, IV, and V in our study. In class II LN, IFTA was found in lower range, while it was worst in class IV (40%). Class I had no IFTA.
Overlapping features were present in six (5.76%) cases in this series which include LN IV + V in four and LN III+V in two cases. Farah et al reported overlapping LN classes in 8.9% of cases and Singh et al reported combination in 3.84% of cases.[10],[15]
In this series, the mean AI was 4.59 ± 2.06 in class III and 8.71 ±3.41 in class IV LN. There was a mean CI of 2.74 ± 1.31 in class III LN and 3.54 ± 1.58 in class IV LN. Yu et al in their study found AI 8.75 ± 2.73, 10.93 ± 3.36 and CI 2.9 ± 0.97, 3.29 ± 2.03 among class IV-S and IV-G LN, respectively.[20]
In our study, we have reported two (1.92%) cases of TMA and both were found in class III LN. Song et al, in their study, reported TMA in 24.38% of cases[22] and Kotb et al reported TMA in 14% of cases of LN.[23] The significant low incidence of TMA in our study might be due to racial variation and the cause needs to be evaluated by further study.
Our study also reveals one case of amyloidosis in the cohort, which is reportedly a rare association with LN.[24] As the patient is of class II LN, possibly it is an incidental association in our case.
Conclusion Among different histological classes of LN, the prevalence of class IV was more in this study which had the most severe form of clinical presentation (hematuria), biochemical parameters (raised serum creatinine level), and histological findings (crescent formation and IFTA). In our study, the correlations of clinical manifestations and laboratory findings with ISN/RPS classes of LN in a group of Bangladeshi patients were analyzed. We found that some demographic, clinical, and laboratory findings were different from those in previous studies of LN. This correlation may help to determine the prognosis and the need for immediate immunosuppressive treatment. Clinical manifestations and laboratory results are helpful in the prognosis and prediction of clinical courses. Renal biopsy remains the cornerstone for identifying treatment options for LN patients. This study provides more information about LN in Bangladesh and future clinical research.
Conflict of interest: None declared.
References 
Correspondence Address:
Sk Md Jaynul Islam
Department of Histopathology, Armed Forces Institute of Pathology, Dhaka, Bangladesh.
Bangladesh
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/1319-2442.352438
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