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Lupus vasculopathy- An underappreciated pathology Khandelwal GK, Sengupta M, Basu K, Roychowdhury A



How to cite this article:
Khandelwal GK, Sengupta M, Basu K, Roychowdhury A. Lupus vasculopathy- An underappreciated pathology. Indian J Pathol Microbiol 2022;65:487-90




Dear Editor,

Lupus nephritis (LN) is the constellation of glomerular, tubulointerstitial, and vascular injury. Although the glomerular changes overcast in pathological classification and scoring system, but the presence of vascular damage negatively impacts the clinical course.[1] Klemperer in 1941 first highlighted their existence and morphological categorization was elaborated by Appel G, et al.[3] in 1994 which include vascular immune complex deposition, noninflammatory necrotizing vasculopathy, thrombotic microangiopathy, and true renal vasculitis.[2] Noninflammatory necrotizing vasculopathy also known as lupus vasculopathy is an uncommon form of renal microvascular lesion and characterized by reduction of luminal diameter by endothelial swelling, denudation accompanied by collection of immune-complex and fibrin-related products. Although pathogenesis is not well established, stimulation and dysfunction of immune system and endothelial cells are postulated.[4] Due to scarcity of literature from our population, we take the opportunity to report a case of lupus vasculopathy with combined LN class III and V presented with accelerated hypertension.

A 26-year-old female came with chief complaints of generalized body swelling and frothing of urine for 4 months. There was shortness of breath and chest pain along with decreased urine output for 15 days. The patient was apparently alright 4 years back and then she started to develop generalized body pain. She was also having hair fall. She also had complaints of malar rashes on exposure to sunlight. For the above complaints, she was taking treatment [prednisolone and hydroxychloroquine sulfate (HCQS)] from a local physician. Her symptoms were relieved on those medications. But she stopped treatment one and half year back while she became pregnant. Her pregnancy was uneventful. She delivered full term with uneventful postpartum period. No complaint of chest pain associated with sweating or feeling of impending doom. She had no complaint of fever, sore throat, or skin infection prior to illness. There was no history of diarrhea, vomiting, blood in stool prior to illness. She was not suffering from any chronic illness. Family history of such illness was also not documented.

There was no associated fever, arthralgia, headache, visual disturbances, psychosis, or seizures or loss of consciousness. Mucosal ulcer was noted. Progressive decline in urine output was reported. General physical examination showed pallor with appreciable pedal oedema. Her pulse rate was 90 beats per min, blood pressure of 200/120 mm of mercury, and respiratory rate of 18 breaths per minute. Systemic examination was unremarkable. Laboratory workup revealed abnormal renal function with a baseline creatinine of 1.38 mg/dL and serum blood urea nitrogen (BUN) 48 mg/dL. Her serum albumin was 3.7 g/dL. Hemogram showed hemoglobin of 8.8 gm/dL, total leukocyte count of 8.8 × 109/L with a normal differential count and platelets of 1.90 × 109/L. Urine examination revealed 4+ albumins, occasional RBCs. Twenty-four-hour urine proteins were 7 g/total volume (2600 mL). Fasting blood sugar was 210 gm/dL. Liver function tests were within normal limits and coagulation workup revealed a prothrombin index of 100%. Lipid profile showed that serum total cholesterol was 334 mg/dL. Serum complement levels were reduced (C3 = 65 IU/L and C4 = 14 IU/L). His ANA was 3+ homogenous, but serum ANCA and anti- GBM were negative. Human immunodeficiency virus, hepatitis B surface antigen, and antihepatitis C virus antibodies were negative [Table 1].

Under ultrasound guidance, renal biopsy was performed. Two tissue cores were obtained and delivered into two separate containers (buffered formalin and cold normal saline) for both light microscopic and immunofluorescence examination. For light microscopic evaluation, two trained nephropathologists examined four separately stained sections according to standard protocol [Hematoxylin and eosin (H and E), periodic acid-Schiff (PAS), silver methanamine (SM), and Masson Trichrome (MT) stains]. Frozen sections were performed for immunoflourescence examination. Total seventeen glomeruli were identified among which three were segmentally sclerosed (NOS) with adhesion. Rest and the nonsclerosed tufts showed diffuse and global mesangial hypercellularity. Segmental endocapillary proliferation was identified in four glomeruli. Neutrophilic infiltration was detected in all glomeruli. Intracapillary hyaline immune thrombi were identified in two glomeruli. Cellular crescents were noted in two glomeruli. Glomerular basement membrane was uniformly thickened with the presence of spikes in silver methanamine stain. Segmental wire loop lesion was identified in six glomeruli. Tubules revealed mild atrophy identified with colloid cast. Interstitium showed mild fibrosis with sparse lymphoplasmacytic infiltration in scarred interstitium seen. Lumen of a preglomerular arteriole was severely narrowed by intimal deposit of intensely eosinophilic material suggestive of fibrin due to fuschinophilia in an MT-stained section. Interstitial fibrosis and tubular atrophy was 10%. Immunoflourescence findings of glomerular and extraglomerular compartments were analyzed and revealed 15 glomeruli with IgG (2+), IgA (2+), C3c (2+), C1q (2+), kappa (2+), lambda (3+) granular deposition in mesangial and along glomerular basement membrane. IgM positive intracapillary thrombi were also noted. Focal proliferative and crescentic glomerulonephritis with membranous pattern of injury was the morphological finding. Considering immunoflourescence, final impression of LN class III (A/C) + V was formed. Modified NIH activity score was 8/24, and chronicity score was 3/12. Lupus vasculopathy (noninflammatory necrotizing vasculopathy) was an additional finding [Figure 1], [Figure 2], [Figure 3].

Figure 1: Histopathology of the kidney biopsy. (a) Light microscopy (SM stain, 100 ×). Mesangial and endocapillary proliferation, duplication of glomerular basement membrane and/or “wire loop” lesions and crescents. (b) Light microscopy (SM stain, 200 ×). Cellular crescent. (c) wire loop lesion (MT stain, 200 ×). (d) Cellular crescent (PAS stain, 200 ×)

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Figure 2: Histopathology of the kidney biopsy. (a) Light microscopy (HE stain, 200 ×). Intraluminal eosinophilic hyaline-like material without any inflammatory cell infiltrate in one preglomerular arteriole. Inset showed immunofluorescent study using frozen section (200 ×). Strong perivascular staining of IgG. (b-d) Light microscopy (c PAS stain, d Masson’s trichrome stain and SM stain, 200 ×)- PAS positive and fuchsinophilic deposit. SM stained section show near total occlusion of the lumen

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Figure 3: Immunofluorescent study (FITC labelled IgG, IgA, IgM, C3c, C1q, kappa and lambda; 200 ×) using frozen specimen. Coarse granular staining along GBM and mesangium

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Before starting immunosuppressant, ANA profile was sent, and scleroderma was ruled out as the patient presented with accelerated hypertension. As the patient was a serologically confirmed case of SLE, and the patient had nephrotic range proteinuria, the patient was kept on oral steroid along with antihypertensive – calcium channel blocker, diuretics, and beta blocker. As soon as the biopsy report became available, cyclophosphamide was started as per the NIH protocol. In the first month of the induction therapy, the patient had one episode of rise of creatinine, which was found to be due to hypoalbuminemia-related acute kidney injury or due to disease activity itself. She was treated with slow continuous ultra-filtration with intravenous albumin also. At the end of second month of induction therapy, she attained her creatinine level almost at her baseline level. She started showing good diuretic response also [Figure 4].

Vascular involvements develop during disease course remarkably worsen the quality of life and causes mortality in SLE. Renal, coronary, mesenteric, and cerebral microvasculatures are most commonly involved. Renal vascular complication of LN are broadly categorized into five subtypes -(I) arteriosclerosis, (II) uncomplicated vascular immune deposits, (III) noninvasive necrotizing vasculopathy, (IV) thrombotic microangiopathy, and (V) true vasculitis.[3] Non inflammatory necrotizing vasculopathy also known as lupus vasculopathy is a rarely encounter form. Although vascular lesions were reported by previous literatures with a variable incidence ranging from 10% to 40%, lupus vasculopathy accounts for 3.8% to 9.5% of all.[5] Over attention to glomerular changes leads to misdiagnosis of this focal lesion. Association with accelerated hypertension and rapidly progressive renal failure make it an unfavorable prognostic factor and demands critical evaluation of renal vascular pathology during native biopsy reporting.

Severe active class of lupus nephritis is the most commonly identified along with this vascular pathology.[6] Ishizaki Y, et al. reported a case of lupus vasculopathy with combined LN class IV + V occurring in a middle-age woman.[1] We also share similar experience in a young woman suffering from combined LN class III (A/C) + V. Preglomerular arterioles are chiefly involved with characterized accumulation of eosinophilic acellular materials resulting in occlusion of the lumen. We have also demonstrated similar location and morphology. Immunoflourescence microscopy also revealed discrete perivascular IgG deposition. In addition to intimal changes, damage to medial myocytes is also evident in some cases. Absence of inflammatory response and sparing of medium caliber vessels helps to differentiate it from true vasculitis.[7] However, distinguishing from acute phase of thrombotic microangiopathy (TMA) is sometimes difficult. Involvement of adjacent glomerulus and absence of immune complex deposition are constant features in thrombotic microangiopathy.

The pathogenesis of this vaso-occlusive change is yet to be established. Presence of confluent electron dense immune deposit supports the theory of immune-mediated injury due to precipitation of excessive immune complex within the lumen.[7] Lack of inflammatory response in spite of the presence of immune complex deposit is the riddle. Hypertension plays a role or vice versa. Hypothesis of involvement of coagulation cascade and endothelial injury is also proposed due to clinical overlapping features with TMA. Presence of anti-phospholipid antibody is crucial for thrombotic event; however, it was not detected in our case.

Therapeutic options are not standardized for renal microvascular lesions. Glomerular injury is chiefly addressed in management protocol. Recommendation for hemolytic uraemic syndrome (HUS)/thrombocytopenic purpura (TTP)-associated TMA lesions is available in the Kidney Disease: Improving Global Outcome (KDIGO) guideline.[8] Although immunosuppressant is the baseline therapy, plasmapheresis helps to remove excess immune complexes and defective circulating factors such as complements and coagulation factors. New researches have enlightened the pathogenesis-based approach using anti-endothelial cell antibodies (AECA), anti-oxidized LDL antibodies, and anti-HDL antibodies.[9]

In conclusion, here we describe one case of lupus vasculopathy in the context of adult onset nephrotic syndrome with accelerated hypertension. As this lesion is rare and shows subtle focal changes, the diagnosis can be missed if one is not aware. Critical appraisal of combined light microscopic and immunoflourescence finding is essential to the guide clinician to initiate appropriate therapy.

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   References   Top


1.
Ishizaki Y, Aizawa A, Ochiai S, Minakawa A, Miyauchi S, Umekita K, et al. A case of lupus vasculopathy presenting favorable renal outcome. CEN Case Rep 2020;9:74-80.  Back to cited text no. 1
    
2.
Klemperer P, Pollack AD, Baehr G. Pathology of disseminated lupus erythematous. Arch Pathol 1941;32:569-631.  Back to cited text no. 2
    
3.
Appel GB, Pirani CL, D’Agati V. Renal vascular complications of systemic lupus erythematosus. J Am Soc Nephrol 1994;4:1499-515.  Back to cited text no. 3
    
4.
Mejia-Vilet JM, Cordova-Sanchez BM, Uribe-Uribe NO, Correa-Rotter R, Morales-Buenrostro LE. Prognostic significance of renal vascular pathology in lupus nephritis. Lupus 2017;26:1042-50.  Back to cited text no. 4
    
5.
Kaul A, Agrawal V, Bhaduaria D, Agrawal V, Prasad N, Gupta A, et al. Vasculitis and vasculopathy in lupus nephritis: Clinical variability, outcome, and new insight into treatment. Saudi J Kidney Dis Transpl 2017;28:415-24.  Back to cited text no. 5
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6.
Gonzalez-Suarez ML, Waheed AA, Andrews DM, Ascherman DP, Zeng X, Nayer A. Lupus vasculopathy: Diagnostic, pathogenetic and therapeutic considerations. Lupus 2014;23:421-7.  Back to cited text no. 6
    
7.
Seshan SV. Lupus vasculopathy and vasculitis: What is the difference and when do they occur? Pathol Case Rev 2007;12:214-21.  Back to cited text no. 7
    
8.
Ding Y, Tan Y, Qu Z, Yu F. Renal microvascular lesions in lupus nephritis. Ren Fail 2019;42:19-29.  Back to cited text no. 8
    
9.
Atehortua L, Rojas M, Vasquez GM, Castano D. Endothelial alterations in systemic lupus erythematosus and rheumatoid arthritis: Potential effect of monocyte interaction. Mediators Inflamm 2017;2017:9680729.  Back to cited text no. 9
    



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Correspondence Address:
Moumita Sengupta
244 AJC Bose Road, Kolkata – 700 020, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_1076_20

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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
 
[Table 1]

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