|Year : 2016 | Volume
| Issue : 1 | Page : 15-21
Histopathological study of lupus nephritis with special reference to nonlupus nephritis, focal segmental glomerulosclerosis, interstitial nephritis, and amyloidosis
Usha Singh1, Chhaya Rani Shevra1, Rana Gopal Singh2, Jai Prakash2, Shivendra Singh2, Nand Kumar Singh3
1 Department of Pathology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
2 Department of Nephrology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
3 Department of General Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
|Date of Web Publication||22-Dec-2015|
Chhaya Rani Shevra
Department of Pathology, MLB, Medical College, Jhansi - 284 128, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Context: Lupus nephritis (LN) is the involvement of kidney in systemic lupus erythematosus (SLE) where various types of glomerulonephritis (GN) are seen which affects the therapy also. Aims: To find out the frequency of various types of LN and nonlupus lesion in the kidney of SLE patient. Settings and Design: Retrospective analysis. Subjects and Methods: Total 52 cases of LN were studied between the periods of January 2011 and June 2014. Statistical Analysis Used: Calculation of mean and standard deviation. Results: There was female (76.93%) predominance over males (23.08%). In 63.46%, both ANA and dsDNA antibodies were positive. Only 57.69% patient had typical features of SLE and 17.29% patient had only one clinical manifestation to suggest SLE. In rest cases, renal limited SLE with severe anemia was found. Type IV LN was more common (53.84%) while Type III LN, Type II LN, and Type V LN were seen in equal frequency (9.61% each). In 2 cases, a combination of Type V + IV was found. In 5 cases (9.61%), nonlupus type of lesion was seen. It included 2 cases (3.84%) of amyloidosis and 3 cases of severe chronic tubulointerstitial nephritis with focal segmental glomerulosclerosis (5.76% FSGS). Out of 28 cases of Type IV LN, crescentic GN was found in 10 cases (19.23% CGN). In another 44.44% cases, focal crescents were seen in <40% glomeruli. Conclusions: Thus our study concludes that in LN Type IV is the most common LN and nonlupus related lesions, e.g., amyloidosis, and chronic interstitial nephritis and FSGS can also be found in LN.
Keywords: Chronic interstitial nephritis, crescentic glomerulonephritis, focal segmental glomerulosclerosis, lupus nephritis, systemic lupus erythematosus
|How to cite this article:|
Singh U, Shevra CR, Singh RG, Prakash J, Singh S, Singh NK. Histopathological study of lupus nephritis with special reference to nonlupus nephritis, focal segmental glomerulosclerosis, interstitial nephritis, and amyloidosis. CHRISMED J Health Res 2016;3:15-21
|How to cite this URL:|
Singh U, Shevra CR, Singh RG, Prakash J, Singh S, Singh NK. Histopathological study of lupus nephritis with special reference to nonlupus nephritis, focal segmental glomerulosclerosis, interstitial nephritis, and amyloidosis. CHRISMED J Health Res [serial online] 2016 [cited 2019 Nov 22];3:15-21. Available from: http://www.cjhr.org/text.asp?2016/3/1/15/172389
| Introduction|| |
Systemic lupus erythematosus (SLE) is a chronic systemic, non-organ specific autoimmune disease that follows a course of alternating exacerbation and remissions. It involves multiple organs, e.g., joints, muscle, skin, serosal membranes, kidney, lung, heart, blood vessels, nervous system, eye gastrointestinal, and hematopoietic system.,, About 50–60% of SLE patients will develop the renal disease during their course and 25–50% patient of SLE have the clinical renal disease at onset., Renal lesions in SLE show the various type of glomerulonephritis (GN) which is called as lupus nephritis (LN). In 2003, a new classification of LN was proposed by Weening et al. and published in 2004 which was jointly made by the effort of International Society of Nephrology and Renal Pathology Society working group. This classification includes original 1974 and1982 classification.
In the present classification, LN was classified as Class I (minimal mesangial LN), Class II (mesangial proliferative GN), Class III (focal LN) (active, active + chronic, chronic), and Class IV (diffuse LN). It is further divided into Class IV-S (segmental) and IV-G (Global). In Class IV-S where more than 50% of involved glomeruli has segmental lesion while in IV-G, >50% glomerular tuft have global region. In Class V LN (membranous LN) global or segmental continuous subepithelial deposits with or without mesangial alteration are seen. Class VI is advanced sclerosing GN. It is diagnosed when ≥90% glomeruli show global glomerulosclerosis.,
Aim of this study is to see various histopathological lesions in LN and study of its clinical and biochemical findings.
| Subjects and Methods|| |
Total 52 cases of LN were studied between January 2011 and June 2014. Renal biopsies were preserved in 10% formalin, paraffin blocks were prepared and 2μm thick sections were stained with hematoxylin and eosin, periodic acid-Schiff, and acid Fuschin Orange G stain (AFOG). The later stain was used to see deposits in glomerular basement membrane, mesangium, and thrombi. Thrombi appeared Orange-red in color, and immune deposits appeared red in GBM mesangium and tubular basement membrane. Although the type of deposit immunoglobin G (IgG), IgA, and IgM was not identified by this stain. In five cases of Type IV LN direct immunofluorescence was performed which showed heavy, irregular, and lumpy deposits in GBM and mesangium with all anti IgG, IgA, IgM, and C3 and C4 antibodies (full house syndrome). Clinical details regarding malar rash, discoid rash, photosensitivity, oral ulcer, psychiatric problem, anemia, petechial hemorrhage, abortion, joint pain, swelling body, fever, etc., were recorded.
About 5 ml of blood was taken in a direct, plain vial for ANA, dsDNA antibodies, antineutrophil-cytoplasmic antibody (ANCA), and anticardiolipin antibodies. These autoantibodies were done by ELISA Kit. In crescentic GN cases, ANCA against PR3 and myloperoxidase (MPO) antigen were done by Blue dot kit principle of which was based on enzyme immunoassay.
In ELISA test and immunodot, test instruction of kit was followed. In ANA ratio of above 1.4, and dsDNA dsDNA Ab value 55 IU/ml, APLA value above 15 GPL/ml, were taken as a positive test.
Diagnosis of SLE was made by modified ARA criteria of 1997. This included 11 criteria of which if 4 or >4 are positive than a diagnosis of SLE is confirmed.
| Results|| |
The majority of patients were female (76.93%), and only 23.08% were males. Majority of women patients (77.50%) were between 15 and 40 years while only 58% males were in this age group [Table 1].
Nephrotic range proteinuria was seen in 59.62% cases. Urine microscopic examination revealed microscopic hematuria in 94.23% and leukocytoturia in 65.39%. In 33 cases (63.47%), both ANA and dsDNA antibodies were positive while in 36.54% only ANA was positive. MPO positivity was seen in 2% of cases. Moreover, PR3 ANCA was positive in 3% of cases. Anticardiolipin antibody was positive in 4% of cases [Table 2].
In hematological tests, only three patients had normal hemoglobin (Hb) between 11.5 and 13.5 g/dl and one male patient had very high Hb of 17 g/dl, while rest 48 patients had Hb between 4.2 and 10 g/dl. Total leukocyte count (TLC) was reduced by 15.39% while 7.70% patient had leukocytosis and majority of the patient had normal TLC [Table 3].
Thirty patients out of 52 cases (57.69%) had typical clinical features of SLE in the form of malar rash, discoid rash, photosensitivity, oral ulcers, gangrene of finger, recurrent abortion, anemia, arthritis, pleural effusion, psychiatric symptoms edema of feet and face, etc. These 30 patients had 4 or more than 4 clinical features along with renal symptoms, ANA, and dsDNA or APLA or anti-Sm antibody positivity, thrombocytopenia, anemia, or leukopenia.
In 9 patients (17.29%), only one symptom was present to suggest SLE along with pedal edema or anasarca with and without nausea, vomiting, weakness, and oliguria. One patient out of 52 (1.92%) presented with hemoptysis, one (1.92%) presented with loss of vision, one (1.92%) had psychosis, one (1.92%) had deep vein thrombosis of right lower limb, and one (1.92%) had pain in abdomen along with infarct in para-aortic lymph node. Two patients (3.84%) had hepatosplenomegaly, moderate jaundice along with renal failure.
About 13 patients (23.07%) had renal limited SLE in which no symptoms related to SLE was present. SLE was suspected after renal biopsy finding. They were diagnosed SLE when hematological, and immunological tests were done. These patients fulfilled four or more than four criteria's required for the diagnosis.
In histopathological study most common type of LN was Type IV LN (53.84%) followed by Type II, III, and Type V, (9.62%), while combination of Type IV + Type V LN (mixed LN) was seen in 3.84% of cases. In Type V + VI LN, more than 50% glomeruli had deposits in mesangium and in the subepithelial region while some capillary also had subendothelial deposits. In one case (1.96%), more than 90% glomeruli were hyalinized hence was kept in VI Type. One case (1.92%) was diagnosed as minimal mesangial GN (Type I LN) [Table 4]. This case presented with nephrotic syndrome along with anemia, hematuria, and polyarthritis, on and off rashes for the last 2 years.
In histopathological examination, majority of glomeruli did not show any renal lesion but in AFOG stain mesangial deposits were seen in some glomerulus. In interstitium, there was severe mononuclear cell infiltrations. Tubules also had cellular and pus cell cast. This case was diagnosed as minimal change GN with pyelonephritis [Figure 1]. Collagen profile was done, in which ANA and dsDNA were found to be positive, but urine culture was negative. All cases of Type II LN had segmental moderate mesangial cell proliferation and deposits in more than 50% of glomeruli [Figure 2]a.
|Figure 1: Type I lupus nephritis showing normal cellularity of glomerulus, periglomerular fibrosis and surrounded by dense infiltrate of mononuclear cells and few neutrophils (H and E, ×500)|
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|Figure 2: Type II lupus nephritis having segmental mesangial proliferation (H and E, ×500), (a) Type II lupus nephritis showing mesangial deposit of immunoglobin G (DIF, ×400)|
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All 5 cases of Type III LN had focal segmental endothelial and mesangial cell proliferation with focal GBM thickening. All had active4 lesion in the form of leukocytic infiltration, nuclear karyorrhexis, hematoxylin body, or wire loop lesion [Figure 3].
|Figure 3: Type III lupus nephritis showing segmental endocapillary proliferation, nuclear karyorrhexis and occasional wire-loop lesion (H and E, ×500)|
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Out of total 28 cases of Type IV LN, 18 cases (34.61%) had diffuse proliferative GN. Four out of 18 cases (22.22%) had typical features of mesangiocapillary GN in the form of mesangial cell proliferation lobular appearance of tuft, GBM thickening, and duplication with mesangial cell interposition. In rest 14 cases, there was predominantly endothelial and mesangial cell proliferation [Figure 4]a. In this group also focal GBM thickening was seen in 60% cases with both sub endothelial and few subepithelial deposits.
|Figure 4: Type IV lupus nephritis active lesions having diffuse proliferations of endothelial cells, mesangial cells, and nuclear karyorrhexis. One of the arteries shows the thrombus (H and E, ×500), (a) heavy and diffuse coarse deposits along GBM and in mesangium of Type IV lupus nephritis (DIF, ×400)|
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About 15 glomeruli out of 18 cases of noncrescentic Type IV (83.33%) had active lesion (A), and 3 (16.6%) had both active and chronic lesion (A + C). Out of 28 cases of Type IV, 10 cases (19.23%) had crescent formation in more than 60% glomeruli [Figure 5]. In one case, only focal semilunar crescent formation was present in more than 50% glomeruli along with diffuse proliferation while in the rest of the cases global crescent was present.
|Figure 5: Type IV lupus nephritis showing fibrocellular crescents, moderate increase in mesangial cells and mesangial matrix (H and E, ×500)|
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In 5 cases, Type V LN was found which showed diffuse GBM thickening and focal mesangial cell proliferation. Two of these cases showed the focal proliferation of endothelial and mesangial cell [Figure 6]a. In 3 cases of focal segmental glomerulosclerosis (FSGS), with severe chronic interstitial nephritis were found. Renal pathology showed segmental glomerulosclerosis with periglomerular fibrosis. Tubules revealed focal necrosis, moderate atrophy, and thyroidization. In interstitium, severe mononuclear cells infiltration were present. She was diagnosed as FSGS, with interstitial nephritis and was advised for ANA, ds DNA antibodies, and ANCA. Her ANA, dsDNA antibodies were positive.
|Figure 6: Diffuse uniform deposit in GBM, focal mesangial cell proliferation and nuclear karryorhexis acid Fuschin Orange G stain × 400), (a) Type V lupus nephritis showing finely granular deposit along GBM (DIF ×400)|
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| Discussion|| |
The renal complication in SLE is very common. Autopsy study shows that 75% SLE patient have LN. The renal biopsy performed not only for diagnostic purpose but also for the therapeutic and prognostic purpose. In the present study, female predominated (76.93%) over the males (23.08%) in LN. About 59.56% patient had nephrotic range proteinuria and 94.23% cases had microscopic hematuria.
Our study was more or less similar to the study of Jindal et al. who also found a predominance of female over the males with the mean age of 28 years. Contrary to us they found nephrotic range proteinuria in 66% cases.
In Our study, ANA was positive in all cases but dsDNA antibodies were positive in only 63.47% cases. Contrary to us some study found dsDNA antibodies positivity in about 75% cases. The initially immune complex formed by DNA and anti-ds DNA antibodies was supposed to be main mechanisms of renal injury. However, recently few study reported that antichromatin antibody also called as anti-nucleosome antibodies are associated with renal involvement. This antibody is responsible for the formation of LE cells in vitro and is found in 75% cases of the whole SLE. Our study also supports this.
In renal histopathology, in our study the most common type of LN was of Type IV LN (53.18%) followed by Type II, Type III, and Type V (9.62% each). In two cases, Type V LN was accompanied by segmental endocapillary proliferation in 50% glomeruli. It was labeled as Type V + Type IV LN. Only one case (1.92%) of Type I LN was accompanied by severe tubulointerstitial nephritis (TIN).
More or less similar to our finding, study from Jindal et al. also found predominance of diffuse proliferative LN (51.86%) followed by Type III, Type II, and Type I LN (11.12%each), Type IV LN (7.41%) and Type V LN (3.71%).
More or less similar to our study one Western study, found higher frequency of Type III and Type IV LN in 55% cases followed by 25% cases of Type II LN and 15% of Type V LN. They described that 5% LN could not be identified.
In our cases, 19.23% of Type IV LN was categorized as CGN because more than 60% glomeruli had crescent formation while another 44% patient of Type III + IV had focal crescents in <40 glomeruli. A study from North Carolina USA also found that 11% of LN showed more than 50% crescent and 31% LN have focal crescent. Similar study from Bangkok reported that LN accounted for 51.6% of total CGN. A study from New York also describes 20% frequency of necrotizing cresentic GN in LN patients. Another study from china found (Yu et al. 2009) that Type IV LN in only 46.09% which also included 10% cases of CGN, they found that 100% cases of CGN had acute renal failure and very high ANCA positivity and in these cases complete remission was poor.
We also found nonclassified lupus renal lesions in 7.68% cases. Two cases (3.84%) had amyloidosis, and three cases had FSGS with severe chronic interstitial nephritis. In our present study 5.79% cases histopathology did not belong to classical LN, it included FSGS with TIN and amyloidosis. All 3 cases of FSGS were female and had nonnephrotic range proteinuria.
Amyloidosis in SLE is rare it may involve kidney, lung, or gastrointestinal tract. Both of these cases were known cases of SLE for several years. Like us, Baronwska-Daca et al. 2001 from USA also found that 2.52% of SLE nephrotic cases showed non LN. They found five cases of FSGS in 224 cases of SLE. Depending upon disease activity divided renal lesion into three groups. Baranoska-Deca et al., also did follow-up of 5 cases which included one case of focal proliferative, 2 cases of mesangioproliferative and one case of diffuse proliferative LN. Biopsy done after few years showed that two out five cases turned into FSGS.
Similar to us there are many case reports, Ogusa et al. 1992, Hills et al. 2001, Daniel et al. 2001, Kumar et al. 2010 who found that patient of SLE may show feature of severe TIN in histopathology, instead of classical GN.
Thus, our study concludes that nonlupus lesion of TIN with FSGS and amyloidosis can occur in SLE. The presence of amyloidosis, severe tubulointerstitial inflammation in the biopsy suggest that chronic inflammation may be responsible for SLE.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4]