|Year : 2017 | Volume
| Issue : 2 | Page : 415-424
|Vasculitis and vasculopathy in Lupus Nephritis: Clinical variability, outcome, and new insight into treatment
A Kaul1, V Agrawal2, D Bhaduaria1, Vikas Agrawal3, Narayan Prasad1, Amit Gupta1, RK Sharma1
1 Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
3 Department of Immunology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
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|Date of Web Publication||23-Mar-2017|
| Abstract|| |
More than 50% of patients with systemic lupus erythematosus (SLE) have renal involvement at presentation or during their illness. Lupus nephritis (LN) encompasses several patterns of renal disease, including glomerular, tubulointerstitial, and vascular pathologies. The presence and significance of renal vascular lesions (VLs) are often overlooked. VLs in LN are not rare with an incidence of 10%–40% on renal biopsies from various studies and their presence is often labeled as poor prognostic markers. The current treatment protocol for LN is mainly based on the glomerular pathology, and no guidelines/consensus exists for treatment of LN with VLs. We describe the clinical presentation, course, response to therapy, and outcomes in five patients with SLE with histological evidence of renal VLs.
|How to cite this article:|
Kaul A, Agrawal V, Bhaduaria D, Agrawal V, Prasad N, Gupta A, Sharma R K. Vasculitis and vasculopathy in Lupus Nephritis: Clinical variability, outcome, and new insight into treatment. Saudi J Kidney Dis Transpl 2017;28:415-24
|How to cite this URL:|
Kaul A, Agrawal V, Bhaduaria D, Agrawal V, Prasad N, Gupta A, Sharma R K. Vasculitis and vasculopathy in Lupus Nephritis: Clinical variability, outcome, and new insight into treatment. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2019 Jun 24];28:415-24. Available from: http://www.sjkdt.org/text.asp?2017/28/2/415/202777
| Introduction|| |
More than 50% of patients with systemic lupus erythematosus (SLE) have renal involvement at presentation or during their illness.,, Conventionally, in lupus nephritis (LN), the main focus in on glomerular pathology, as evident in the histopathological classification by the International Society of Nephrology and Renal Pathology Society. The presence and significance of renal vascular lesions (VLs) are often overlooked. Varieties of histopathological lesions of renal vessels as well as a number of distinct clinical syndromes have been described by Appel et al in LN. VLs in LN are not rare with an incidence of 10%– 40% on renal biopsies from various studies and their presence is often labeled as poor prognostic markers.,, The current treatment protocol for LN is mainly based on the glomerular pathology, and no guidelines/consensus exist for treatment of LN with VLs.
Herein, we describe five patients of SLE with histological evidence of renal VLs, their clinical presentation, course, response to therapy, and outcome.
| Case Reports|| |
A 25-year-old woman with no previous illness/comorbidities presented with complaints of recurrent oral ulcers for since five months, loss of appetite, malaise, and weakness for since three months, pruritic rash in lower limbs and pedal edema for since one month, pain in the small joints of the hand (symmetrical with no early morning stiffness) and bilateral knee joint pain with left knee joint swelling for 15 days. Over the last 10 days, there was reduced urine output with worsening edema and progressive breathlessness. The patient had no history of hematuria, recurrent fetal loss, drug intake, or any family history of autoimmune diseases. The patient had her last pregnancy 18 months earlier, which was uneventful.
On examination, she was pale, tachycardic, hypertensive, and in volume overload with no characteristic skin lesions of lupus. Multiple oral ulcers and bilateral knee joint swelling (left > right) with signs of inflammation were evident on general physical examination. The patient was oliguric at the time of admission. Laboratory findings on admission are shown in [Table 1]. She was diagnosed as a case of SLE with LN (probable Class III/IV) with pancytopenia. Her SLE disease activity index (SLEDAI) score was 28.
|Table 1: Laboratory parameters of the study patients at initial presentation.|
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In view of deranged coagulation profile, severe anemia, and thrombocytopenia, renal biopsy was deferred initially. With a strong clinical suspicion of proliferative glomerulonephritis, she was empirically started on pulse intravenous (i.v.) methylprednisolone (MP) for three days followed by oral prednisolone at 1 mg/kg. The patient was started on low-dose i.v. endoxan (500 mg) as per the EUROLUPUS protocol. After stabilization of hematological parameters and correction of coagulation profile, the patient underwent an ultrasound-guided renal biopsy on day-10, which was provisionally reported as Class-IV (A) LN with no evidence of crescents and with minimal tubular atrophy and interstitial nephritis. As patient continued to be oligoanuric and dialysis dependent with high titers of anti-dsDNA even on day-14, she was started on weekly cycles of Rituximab (chimeric monoclonal antibody against the protein CD20) (375 mg/m2) for four weeks. By day-16, a full validated report of renal biopsy with immunofluorescence (IF) suggesting an acute diffuse proliferative Class-IV LN with noninflammatory necrotizing lupus vasculopathy was available. Due to ongoing hemolysis (fragmented cells in peripheral smear, high reticulocyte count, and serum lactate dehydrogenase), persistent oliguria and renal biopsy suggestive of lupus vasculopathy, the patient was started on plasmapheresis. By day-27, she had completed five cycles of alternate day plasmapheresis and continued to be on daily oral steroids, weekly rituximab and fortnightly dose of i.v. cyclophosphamide. Even though she remained dialysis dependent, the frequency of dialysis was reduced, her urine output improved, and hemoglobin stabilized with no evidence of hemolysis. By week-5, the patient had become dialysis independent and her serum creatinine showed a declining trend. During this period, she received hydroxychloroquine, anti-fungal agents, and prophylaxis against Pneumocystis carina
By week-10, her serum creatinine was 1.8 mg/dL and had achieved partial remission (U. pr/U. cr = 0.8). After five months (end of intensive phase), her serum creatinine was 1.0 mg/dL, and she had achieved complete remission with anti-ds-DNA titer of 32 IU/mL. The dose of steroids was tapered at regular intervals and she was started on mycophenolate mofetil (MMF) as maintenance immunosuppressive drug. She has been on follow-up for over two years and has a normal renal function with no relapse.
A 30-year-old housewife, mother of two children, presented with complaints of excessive hair loss, nonpruritic skin rash over malar area, trunk and back and low-grade intermittent fever for six months. Over the last six weeks, the patient had oral ulcers, and difficulty in getting up from the chair. In addition, she had pain and swelling of multiple joints in both upper and lower limbs. She had no history of any recent drug intake, skin tightening, abdominal pain, hematuria, pedal edema, reduced urine output, seizure, or sensory abnormalities. In the past, she has had two induced abortion and one spontaneous first-trimester abortion.
On examination, she was normotensive and had normal general physical and systemic examination except for swelling and tenderness of small joints of the hand and feet and restriction of movements in the shoulder joint. Her laboratory findings on admission are shown in [Table 1]. Based on her clinical history and laboratory results, the patient was diagnosed as a case of SLE with LN and hepatitis. Her SLEDAI score was 25. She underwent a renal biopsy and was started on low-dose EUROLUPUS protocol with i.v. MP pulses followed by oral steroids. Over the next one month, her liver enzymes became normal. The patient had achieved complete remission with normal renal function at the end of six cycles of cyclophosphamide and has sustained remission after 18 months of follow-up.
A 45-year-old housewife, mother of three children with last pregnancy 10 years ago, presented with complaints of polyarthralgia involving all four limbs for one year. Joint pain was present in both small and large joints, was symmetrical, nondeforming and not associated with any joint swelling or early morning stiffness. She had consumed multiple herbal medicines for the above complaints in the last one year. She also complained of recurrent oral ulcers and malar rash for six months. Over the past two months, the patient had progressive pedal and facial edema with worsening dyspnea on exertion. She had no history of skin tightening, cold intolerance, abdominal pain, hematuria, pregnancy loss, seizure, or sensory abnormalities.
On examination, she was pale, edematous and hypertensive. Her laboratory findings on admission are shown in [Table 1]. Based on her clinical history and laboratory results, the patient was diagnosed as a case of SLE with LN and severe anemia. Her SLEDAI score was 29. She was transfused with packed red blood cells and considering a delay in renal biopsy due to thrombocytopenia; she was empirically treated with i.v. MP pulses followed by oral steroids. She underwent a renal biopsy and was started on oral cyclophosphamide (2 mg/kg). By week-10 on oral cyclophosphamide, the patient had achieved partial remission with normal renal function but developed severe pancytopenia and an abscess in the left breast. The cyclophosphamide was stopped. Following recovery from infection, she was shifted to maintenance oral MMF.
A 32-year-old housewife, mother of two children with last pregnancy five years ago presented with history suggestive of Raynaud’s phenomenon in fingers of both hands in the winter of 2008–2009. Six months later, she complained of pain and swelling of bilateral upper limb joints along with bluish discoloration of fingertips. In September 2009, the patient developed recurrent oral ulcers with massive lower gastrointestinal bleed. On evaluation, she was found to have pancytopenia with severe thrombocytopenia. She underwent a bone marrow examination and was diagnosed to have aplastic anemia and required multiple blood transfusions. The patient was then lost for follow-up, and she presented to the immunology clinic in November 2012 with complaints of tightening of the skin and inability to extend her fingers and open her mouth widely. She also complained of erythema over the face in a butterfly shape distribution involving cheeks and nose, on exposure to sunlight. She was unable to comb her hair and to completely extend her shoulders. She had no history of recurrent abortions, hematuria, seizure disorder, alternate drug intake, or long-standing history of painkiller.
On evaluation, she was found to be hypertensive, anemic with mild renal failure (eGFR = 59 mL/min/1.73 m2), and active urine sediment [Table 1]. She also had positive skin and musculoskeletal findings. She was diagnosed as a case of overlap syndrome (Sjogrens + SLE) and was referred to the nephrology department for renal biopsy. Following her renal biopsy, she received three doses of pulse i.v. MP followed by oral steroids and oral MMF. On follow-up, her serum creatinine showed an increasing trend with persistent urinary activity. She was then shifted to the EUROLUPUS protocol.
The patient was then lost to follow-up. She presented to the nephrology clinic four months later with advanced renal failure and uremic symptoms. By this time, she had progressed to end-stage renal disease and is now on maintenance hemodialysis since the last three months.
A 27-year old female with no previous co-morbidities presented with complaints of bilateral pedal edema for one year. Edema progressed and was associated with reduced urine output for two months. In the last six months, she had recurrent oral ulcers and pain in the small joints of the hand. She had no history of rash, fever, abdominal pain, hematuria, pregnancy loss, seizure or sensory abnormalities, drug intake, or any family history of autoimmune diseases. She was evaluated, found to have advanced renal failure and initiated on hemodialysis at the time of referral to our institution.
On examination, she was severely anemic, edematous, and hypertensive with features of volume overload. Her laboratory findings on admission are shown in [Table 1]. Based on her clinical history and laboratory results, the patient was diagnosed as a case of SLE with LN and severe anemia. Her SLEDAI score was 31. She was empirically treated with i.v. MP pulses followed by oral steroids. Following stabilization, she underwent a renal biopsy and received a dose of pulse i.v. cyclophosphamide. The patient was dialysis dependent and was oliguric at the end of 2nd week of hospitalization. With evidence of intravascular hemolysis on peripheral smear and renal biopsy suggestive of vasculopathy, the patient was started on plasmapheresis. She had one episode of generalized tonic-clonic seizures which responded to sodium valproate in the 3rd week of hospital stay. At the end of eight sessions of plasmapheresis, the patient continued to be dialysis dependent and oliguric. Her hemoglobin stabilized, and evidence for continued hemolysis was absent. The patient continued to be dialysis dependent and was discharged on low-dose EURO-LUPUS protocol with oral steroids and hydroxychloroquine at the end of 5th week of hospitalization. The clinical spectrum of the study patients is shown in [Table 2].
| Discussion|| |
In the above cases, we noticed (a) renal histology of proliferative glomerular nephritis with VLs, (b) variable presentation from asymptomatic urinary abnormalities to dialysis-dependent renal failure, (c) positive extractable nuclear antigen screen in three out of five patients. (d) delayed presentation, higher SLEDAI scores and progression to ESRD in Cases 4 and 5 and, (e) favorable response to therapy, achievement of partial to complete remission, and absence of flare on follow-up in Cases 1, 2, and 3.
VLs in renal biopsies of patients with LN are not uncommon and their presence in renal biopsies is considered as a marker of poor prognosis in LN., In a review by Appel et al in 1994, five morphologic forms of lupus VLs have been described: (a) uncomplicated vascular immune deposits, (b) nonspecific arteriosclerosis, (c) noninflammatory necrotizing vasculopathy, (d) thrombotic microangiopathy (TMA), and (e) true renal vasculitis.
Widespread activation of vascular endothelium forms the primary pathogenic mechanism accompanied by abnormal expression of markers of activation, including adhesion molecules such as VCAM-1, E-selectin, and inducible nitric oxide synthase.,, Measurement of levels of circulating endothelial cells and circulating levels of the endothelial protein C receptor has been used in various studies for predicting VLs in LN., However, renal biopsy continues to be the gold standard for classifying renal VLs in LN.
Uncomplicated vascular immune deposits are the most common renal VLs characterized by normal histology by light microscopy with demonstration of granular deposits of immunoglobulin, often associated with C1q or C3. The disease is clinically silent, and they have not been found to confer a higher risk of hypertension or progressive renal disease.,,
Noninflammatory necrotizing vasculopathy affects predominantly preglomerular arterioles and to a lesser extent interlobular arteries, especially in the setting of severe active Class-IV LN. The affected vessels are severely narrowed and sometimes occluded by intimal and luminal deposits of glassy eosinophilic material. Severe hypertension is common and probably exacerbates the vascular changes.,,
TMA shows pathological and clinical manifestations similar to lupus vasculopathy. TMA is usually associated with antiphospholipid syndrome or hemolytic-uremic syndrome (HUS)/ thrombotic thrombocytopenic purpura (TTP) in SLE patients. In contrast to lupus vasculopathy, TMA is thought to be a non-immune and noninflammatory vasculopathy and does not show the deposition of immune complex, particularly IgG, on vascular walls.,, Our patients had immune deposits in the vessel wall and were not found to have antiphospholipid antibodies, lupus anticoagulant, or arteriolar/arterial thrombosis in their renal biopsy specimen, suggesting that their renal VLs were not likely to be related to TMA. Arteriosclerosis may cause similar VLs, but in our cases, the deposition of IgG was identified in the renal arteriole. Since IgG is not non-specifically trapped in vessels with ordinary arteriosclerosis or arteriolosclerosis, an immunemediated process might be involved in the pathogenesis of VLs.
True lupus vasculitis is the least common VL in LN. Histologically, they are indistinguishable from that seen in polyarteritis nodosa or microscopic polyangiitis (overlap vasculitis). Morphologically, these lesions are the only form of lupus VL yet described, in which there is true inflammatory infiltration of the intima and media by neutrophils and mononuclear leukocytes, often accompanied by fibrinoid necrosis and rupture of elastic lamellae. IF discloses strong staining for fibrin-related antigens with weak and more variable staining for immunoglobulin and complement. This lesion may occur in any class of active or inactive LN.,,, Renal biopsy from Case-2 had inflammatory vascular infiltration [Figure 1] and [Figure 2] of the interlobular artery with accompanying fibrinoid necrosis.
|Figure 1: Renal histology from a patient with lupus nephritis showing lupus vasculopathy involving an interstitial artery (arrow), characterized by transmural eosinophilic fibrinoid material (Periodic acid Schiff, ×400).|
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|Figure 2: Lupus vasculopathy on renal histology in patients of lupus nephritis. It is involving the interlobular arteries and is characterized by non-inflammatory transmural eosinophilic fibrinoid material. The involvement is partial (a) to circumferential (b) and focally associated with fragmented red blood cells (c) (a-c: H and E,×400). The deposits are fuchsinophilic on periodic acid-Schiff stain (d: ×400).|
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In most series, lupus vasculopathy carries an ominous prognosis, with frequent, severe renal insufficiency, active urinary sediment, active lupus serologies, hypertension, and rapid progression to renal failure.,, The treatment of lupus vasculopathy has not been established, however, as it almost invariably associated with active proliferative lupus glomerular lesions aggressive immunotherapy is advocated.,, In Cases 1 and 5, the patients were initially treated with high-dose steroids and cyclophosphamide. Since the patient continued to be oliguric with high serum creatinine and peripheral evidence of hemolysis at the end of two weeks, aggressive immunosuppression targeting reduction in immunoglobulins was used. Accordingly, the patient was treated with plasmapheresis with addition of rituximab in Case-1 as evidence for chronicity was minimal on renal biopsy. Currently, plasmapheresis is not a standard therapy and is sparingly used in LN patients with severe pulmonary hemorrhage, HUS/TTP-like syndrome, APLA with a clotting episode which cannot be anticoagulated due to hemorrhage, lupus cerebritis, and in double positive [lupus + Anti-neutrophil cytoplasmic antibody (ANCA) serology positive] patients. Occasional case reports of acute occlusive vasculopathy secondary to SLE in various organs have been successfully treated with plasma exchange and rituximab.,,
Rituximab has been used as “off-label” therapy in SLE and other systemic autoimmune diseases. Specific B-cell depletion therapy with rituximab improves peripheral B-cell abnormalities in SLE patients and is associated with a reduction in anti-dsDNA and anti-nucleosome antibody levels. There is no standard therapeutic regimen in SLE, but the most frequently used are the ones recommended for the treatment of lymphoma (375 mg/m2 of rituximab weekly for 4 weeks) and rheumatoid arthritis (two 1000 mg doses separated by 15 days).,
Since this disease is auto-inflammatory driven degeneration of vessel wall, a targeted approach in histological diagnosis and alertness for early clinical signs may prove organ or even life-saving in young patients with more aggressive disease.
In summary, VLs are often overlooked as they may be focally distributed and often excessive attention is directed to the glomerular pathology. More consideration needs to be paid for the VLs in LN because these lesions may be one of the prognostic factors for loss of renal function in LN. Other than the class of glomerular lesion, consideration should be given for the type of VL, and its response to initial therapy and treatment should be further individualized. Delayed presentation has an overall worse outcome and is resistant to treatment. Thus, functional and phenotypic heterogenicity of vascular endothelial lining dictates different types of VLs with variability in clinical presentation, prognosis, and customization of therapy.
Conflict of interest:
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Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh
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[Table 1], [Table 2]
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