—  SPECIALTY CONFERENCE  —

Renal Pathology

Case 2 - Focal Proliferative Lupus Nephritis (W.H.O. III) with Necrotizing Lupus Vasculitis

Gilbert Moeckel
Vanderbilt University Medical Center
Nashville, TN


Click on each slide thumbnail image for an enlarged view
Light Microscopy:
The biopsy specimen contained renal cortical and medullary tissue with 33 glomeruli, 3 of which were globally sclerosed and 1 was segmentally sclerosed. Eleven glomeruli showed segmental endocapillary proliferation (Figure 1) and three of these also showed small fibrin thrombi within capillary lumen. The tubulointerstitial compartment showed mild to moderate interstitial fibrosis with proportional tubular atrophy involving 30-40% of the specimen. In addition there was a focal mixed lymphoplasmacytic infiltrate with few PMNs involving 15-20% of the biopsy. Seven arterioles contained RBC fragments and small fibrin thrombi, four of which were afferent arterioles. One arteriole showed a lymphocytic inflammatory infiltrate of the intima and media with PMNs in the media and karyorrhectic debris. One interlobular artery showed severe vascular injury with lymphocytic infiltrate of the intima and fibrinoid necrosis (Figure 2). Two additional interlobular arteries showed myointimal proliferation with foam cell formation, small fibrin thrombi and almost complete occlusion of the lumen (Figure 3). These arteries also had lymphocytic inflammatory infiltrates of the intima and media with rare PMNs.


Case 2 - Figure 1 -
Glomerulus with segmental endocapillary proliferation (H&E, x 400).
Case 2 - Figure 2 -
Interlobular artery with lymphocytic infiltrate of intima and fibrinoid necrosis (H&E, x 400).
Case 2 - Figure 3 -
Interlobular artery with myointimal proliferation, foam cell formation and almost complete occlusion of vascular lumen (H&E, x 200).



Case 2 - Figure 4 -
Immunofluorescence microscopy. Vascular lesions show strong, chunky staining for IgM (Original magnification x 400).
Case 2 - Figure 5 -
Immunofluorescence microscopy. Vascular lesions show strong, chunky staining for IgA (Original magnification x 400).
Case 2 - Figure 6 -
Immunofluorescence microscopy. Vascular lesions show strong, chunky staining for IgG (Original magnification x 400).



Case 2 - Figure 7 -
Immunofluorescence microscopy. Vascular lesions show strong staining for C1q (Original magnification x 400).
Case 2 - Figure 8 -
Immunofluorescence microscopy. Vascular lesions show strong staining for C3 (Original magnification x 400).
Case 2 - Figure 9 -
Electron microscopy. Ultrastructural examination of an arteriole shows multiple small to medium size immune complex deposits within its wall. There are also small areas of necrosis. (Original magnification x 8000).


Immunofluorescence Microscopy:
IF studies were positive for all Igs (Figures 4-6), and showed 1 to 2+ segmental granular mesangial and capillary loop staining, as well as 2+ chunky arteriolar wall staining for IgG (Figure 6). There was 1+ segmental mesangial and 2+ arteriolar staining for IgA (Figure 5). There was 2+ segmental mesangial and capillary loop staining as well as 1+ arteriolar staining for IgM (Figure 4). There was trace to 1+ mesangial segmental and capillary loop staining for C3. C3 also stained trace to 1+ in arterioles and tubular basement membranes (Figure 7). There was trace segmental mesangial and 1+ arteriolar staining for C1q (Figure 8).

Electron microscopy:
EM studies showed multiple small subepithelial, as well as rare small subendothelial and intramembranous immune complex deposits. There were also multiple small mesangial immune complex deposits. The foot processes were effaced over approximately 30% of the circumference of peripheral capillary loops. There was moderate to severe increase in the lamina rara interna. The endothelial cells were mildly swollen and showed frequent medium to large size reticular aggregates. One arteriole showed fibrin within lumen and arteriolar wall. In addition multiple small to medium size immune-complex deposits were seen (Figure 9). One interlobular artery studied by EM showed fibrin within its lumen and extensive necrosis with myxoid degeneration within the wall. There were also occasional immune complex deposits along the tubular basement membranes.

Differential Diagnosis:
The differential diagnosis includes lupus nephritis with lupus vasculopathy or with lupus vasculitis or with thrombotic microangiopathy, possibly due to lupus anticoagulant or APL syndrome. Furthermore, cryoglobulinemic glomerulonephritis or more remotely HSP should be considered.

Final Diagnosis:
The biopsy diagnosis was focal proliferative lupus nephritis (W.H.O. III) with necrotizing lupus vasculitis.

Discussion:
Vascular lesions are frequently encountered in renal biopsies of patients with SLE and can present in a variety of morphologic forms, including true inflammatory vasculitis, noninflammatory necrotizing vasculopathy, thrombotic vasculopathy, uncomplicated vascular immune deposits and nonspecific arteriosclerosis [1, 2]. A recent large study of patients with lupus nephritis showed that renal vascular lesions were found in 27.7% of the cases, with lupus vasculopathy (9.5%) and thrombotic vasculopathy (8.4%) being most common among these, followed by arteriosclerosis (7%) and vasculitis (2.8%) [2]. Several studies confirm that the presence of renal vascular lesions of the thrombotic, necrotizing or vasculitic type adversely affects renal outcome [2, 3]. True inflammatory vasculitis, which is histologically indistinguishable from that seen in polyarteritis nodosa or microscopic polyangiitis, is rarely seen in patients with lupus nephritis (0.3 to 2.8%) [1, 2, 3]. Some patients present with clinical evidence of systemic vasculitis, yet others appear to have renal limited vasculitis. This form of renal vasculitis has not been studied systematically, owing to the rarity of the lesion and the fact that most of the reported patients antedate the availability of serologic testing for ANCA. Electron microscopic descriptions of these lesions are lacking and it is still unknown whether these vasculitic lesions contain immune complex deposits.

The biopsy of this patient showed focal proliferative lupus glomerulonephritis with 13 out of 41 glomeruli showing segmental endocapillary proliferation, positive staining for all immunoglobulins and complement factors, as well as capillary loop and mesangial immune complex deposits and frequent reticular aggregates. This biopsy also showed an active vasculitic process, with significant leukocytic infiltrate in the intima and media, medial fibrinoid necrosis and rupture of the elastic membrane. The vascular lesions showed immune complex deposits with positive staining for all immunoglobulins and complement factors by IF. The differential diagnosis of vascular lesions in SLE include lupus vasculopathy, thrombotic microangiopathy, lupus anticoagulant or APL syndrome, cryoglobulinemia and the rare true lupus vasculitis.

The biopsy findings in this case differentiate this lesion from noninflammatory necrotizing vasculopathy (i.e. lupus vasculopathy), which presents with severe narrowing of the involved vessel by abundant intimal deposits of glassy eosinophilic material without inflammatory infiltrate, predominantly affecting preglomerular arterioles, and to a lesser extend, interlobular arteries [1, 4].

Thrombotic microangiopathy is another type of renal vascular lesion that may be difficult to differentiate from various types of lupus vasculopathy [1]. It may occur in association with distinct clinical syndromes associated with vascular endothelial damage (i.e. hemolytic uremic syndrome, malignant hypertension, overlap scleroderma) or may be found in renal biopsies of patients with SLE who lack a systemic thrombotic process. However, there is usually no overt leukocyte infiltration of the intima or media and IgG is usually absent from these lesions. This patient's renal biopsy showed 7 arterioles with RBC fragments and small fibrin thrombi, as well as three glomeruli with small fibrin thrombi. Similar arteriolar thrombi, but without vasculitis, were seen in the first biopsy, suggestive then of a thrombotic microangiopathy. Although TMA may be superimposed on virtually any class of lupus nephritis [5, 6], in view of the subsequent biopsy results, the fibrin thrombi more likely were linked to an emerging vasculitic process.

Since the 1980s the lupus anticoagulant or anti- phospholipid (APL) syndrome has been recognized as a major complication of SLE [7, 8]. The kidney is commonly affected in this condition, with overt renal manifestations in approximately 25% of lupus patients with APL syndrome [9]. Renal manifestations range from microthrombosis of glomerular capillaries and arterioles to thrombosis of the main renal artery and vein, with secondary renal cortical necrosis or infarction [10, 11, 12]. These features may produce a spectrum of renal clinical manifestations, including asymptomatic hematuria, mild proteinuria, hypertension, mild renal insufficiency, nephrotic range proteinuria and rapidly progressive renal failure [13, 14, 15]. Overlap of APL syndrome and thrombotic microangiopathy has been described in a variety of classes of lupus nephritis. In a recent study of 26 patients with APL antibodies and renal disease, renal biopsy showed thrombotic microangiopathy with lupus nephritis in 42% of cases with a predominant association to membranous glomerulonephritis [16]. However, serum samples from this patient tested repeatedly negative for the antiphospholipid antibody, making it unlikely that APL syndrome was involved in the vasculopathy.

Necrotizing vasculitis is frequently present in multiple organs of patients with cryoglobulinemia [17]. In a recent study of 44 patients with cryoglobulinemia eight had acute vasculitis with fibrinoid necrosis and leukocytic infiltrates involving afferent arterioles and small interlobular arteries [18]. Cryoglobulin-associated vasculitis is usually associated with deposition of immunoglobulins and complement within the vascular wall [19], or only with immunoglobulins without complement [18]. This patient had negative serum cryoglobulin tests, IgM was not the predominant stain by IF and EM did not show immune deposits with microtubular structure diagnostic for cryoglobuliemia.

Vasculitis with leukocyte infiltration of vessel walls is the least common vascular lesion seen in renal biopsy specimen of patients with lupus nephritis [1]. Prevalence of this form of vasculitis, which cannot be distinguished by morphologic features from entities such as microscopic polyangiitis, has varied from 0.3% [3] to 2.8% [2] in different studies. Some have suggested that lupus vasculitis represents an overlap with other forms of ANCA-related vasculitis. Due to the rarity of lupus vasculitis and the lack of ANCA testing in the rare cases reported this question has not been thoroughly investigated. Morphologically, these lesions are the only type of vascular lesion in SLE 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 internal elastic membrane. Since this patient's ANCA test was negative and immunofluorescence and electron microscopic examinations showed vascular immune complex deposits, an overlap with the pauci-immune vasculitic lesions can be excluded.

In summary, this is a case of renal-limited vasculitis in a patient with active lupus nephritis, that clearly documents ANCA negativity as well as positivity for immune complex deposits by IF and EM within the renal vasculitic lesion. The pathologic and serologic findings in this patient support the conclusion that renal-limited vasculitis in active lupus nephritis is an immune complex-mediated disease process.

Clinical follow-up:
Following the biopsy, the patient was treated with two doses of cyclophosphamide 500 mg i.v. two weeks apart, six plasmapheresis treatments with fresh frozen plasma as replacement, methylprednisolone, and hemodialysis. She developed accelerated hypertension with hypertensive encephalopathy that required intensive care treatment. A follow up renal biopsy one month later showed lupus nephritis in a predominantly mesangial pattern. There was resolution of glomerular proliferative activity without crescents, endocapillary proliferation or thrombi. There were occasional mesangial deposits with rare subepithelial and small intramembranous deposits and occasional tubular basement membrane deposits by EM. Interlobular and large arteries showed moderate intimal fibroblastic proliferation with mucoid change and admixed scattered RBC fragments, consistent with resolving vasculitis without features of the acute necrotizing vasculitic process seen in the previous biopsy. She remains dialysis dependent and on antihypertensive medications.

References

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