Renal Vascular Complications of Systemic Lupus Erythematosus1

Home , Lupus, Renal vein thrombosis, Vasculitis

Gerald B. Appel,2 Conrad 1. Pirani, and Vivette D’Agati

out that, with the exception of cutaneous vasculitis, GB. Appel, CL. Pirani, V. D’Agatl, Departments of true inflammatory lesions of larger arteries are rela- Medicine and Pathology, Columbia-Presbyterian tively uncommon in SLE (3,14,15). Medical Center, New York, NY In our own experience and that of others (15-22), the pathology of the renal vasculopathies seen in SLE (J. Am. Soc. Nephrol. 1994: 4:1499-1515) patients may take several morphologically distinct forms: uncomplicated vascular Immune deposits, noninflammatory necrotizing vasculopathy, throm- enal vascular complications are not infre- botic microangiopathy, and true vasculitis of the mi- quently encountered in systemic lupus cry- croscopic polyarteritis nodosa (PAN) type. thematosus (SLE), and their occurrence can have a profound effect on the clinical course and choice of Vascular Immune Complex Deposits therapy. A variety of histopathologic lesions of the The most common renal vascular lesion in SLE is renal vessels as well as a number of distinct clinical immune complex deposition in the walls of arterioles, syndromes related to vascular damage may occur In SLE. These renal vasculopathies include vascular small arteries, and to a far lesser extent, veins (19,21,23,24). By light microscopy (LM), the vessels Immune complex deposition, noninflammatory necrotizing vasculopathy, thrombotic microangiopathy, usually appear normal. Less commonly, eosinophilic, and true renal vasculitis. The clinical syndromes of periodic acid-Schiff-positive, and fuchsinophilic de- thrombotic thrombocytopenic purpura (TTP), anti- posits are seen beneath the endothelium or between cardiolipin syndrome, and renal vein thrombosis the cells of the media (19). No thrombosis, necrosis, (RVT) are also well-documented vascular coinplica- or inflammatory infiltration of the vessel wall is pres- tions of SLE. Because glomerular pathology is of ent, and the lumen is usually not compromised (Fig- primary importance in the classification of lupus ure 1). By immunofluorescence microscopy (IF), the nephritis, the presence and significance of these vas- deposits may contain immunoglobulin G (IgG), 1gM, cular lesions are often overlooked. Although the path- IgA, and complement components (FIgure 2). By dcc- ogenesis of many of these vascular entities is not fully defined, therapeutic intervention has often been successful. This article reviews their pathology, pathogenesis, epidemiology, and clinical course, as well as the various therapeutic strategies used to treat the vascular complications of SLE.

HISTOPATHOLOGY AND PATHOGENESIS OF LUPUS RENAL ARTERIOPATHIES In the past, the term “lupus vasculitis” was used Indiscriminately and included a variety of arterial lesions involving not only the renal circulation but also the vessels of the upper and lower extremities and the coronary, mesenteric, gallbladder, and cerebral circulations (1-14). Recent studies have pointed Figure 1. Vascular Immune deposits thicken the subendo- Received September 3, 1992. Accepted October 10, 1993. theliai basement membranes of multiple small interlobuiar 2coffe$pondeflce to Dr. G.B. Appel, Department of Medicine, columbia- arteries. The lumen is not significantly narrowed. There is no Presbyterian Medical center. New York, NY 10032-3784. associated inflammation, necrosis, or thrombosis. Uncom- 1046-6673/0408-1499$03.00/0 Journal of the American Society of Nephroiogy plicated vascular immune deposits. Periodic acid-Schiff, copyright C 1994 by the American Society of Nephroiogy x320.

Journal of the American Society of Nephrology 1499 Renal Vascular Complications of SLE

cular (adventitial) deposits present. Such vascular deposits are more commonly found with active gb- merular proliferative forms of lupus nephritis (World Health Organization (WHOI Classes III and IV), typi- cabby in association with tububointerstitial deposits. However, they can also be seen in some cases of mesangial proliferative (Class II) and membranous (Class V) lupus nephritis. They may be overlooked in biopsies because they are often not apparent by LM, because they are focally distributed, and because greater attention is usually directed to the gbomerular pathology. Histologically identifiable vascular deposits may be more common in autopsy specimens, particularly from the presteroid era (19). The pathogenic mechanisms underlying this type Figure 2. By IF, deposits of 196 are detected in the walls of of vascular lesion are probably the same as those several small arteries. Same biopsy as that shown in Figure that mediate gbomerular and tububointerstitial im- 1. Uncomplicated vascular Immune deposits. IF, x400. mune deposit formation. The vascular deposition of circulating immune complexes is a probable mecha- tron microscopy (EM), the deposits are electron dense nism, given the frequency of this vascular lesion in and discrete and often have a granular texture, al- patients with the proliferative forms of lupus gbomer- though occasionally a fingerprint or tactoid substruc- ulonephritis. It is not known whether the in situ ture is seen (Figures 3-5). They are most commonly formation of immune deposits may also play a role. located beneath an intact vascular endothelium or Uncomplicated immune deposits in the wall of small within the basement membranes surrounding the renal arteries may be considered analogous to the medial myocytes (Figure 6). Only rarely are perivas- gbomerular Immune deposits seen in lupus nephritIs

FIgure 3. The same biopsy as that shown in Figures 1 and 2 reveals multiple coarsely granular, electron-dense deposits within the subendotheiIal basement membrane of small arteries. A tubuloreticular inclusion (arrow) is present in the endotheiium. LU, lumen. Uncomplicated vascular immune deposits. Electron micrograph, x#{243},000.

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microscopy will help in differentiating hyalinosis from vascular deposits of immune complexes. Differ- entiation is more difficult when the two diseases are present together.

Noninflammatory NeCrotizing VasCulopathy This type of vasculopathy is much less common than simple vascular immune deposits and may represent a complication of more severe forms of immune complex deposition. It predominantly affects preglomerular arterioles and to a lesser extent the interbobular arteries, frequently in the setting of ac- five, diffuse proliferative lupus gbomerubonephritis. This lesion is characterized by necrotizing changes in the vessel wall associated with abundant immune complex deposits, causing significant luminal narrowing or occlusion (16-20,25,26). By LM, smudgy eosinophilic, fuchsinophilic material that stains focally positive for fibrin occupies the lumen and in- Figure 4. Mauive confluent electron-dense deposits in the intima and media of an arteriole. Uncomplicated vascular tima, with frequent extension into the media. The immune deposits. Electron mlcrograph, x4,500. endothelium is usually swollen or denuded, with occasional pyknotic nuclear fragments and smudgy degeneration of the medial myocytes (Figure 7). The elastic membrane of the interlobular arteries is usually disrupted. Rarely, a few lymphocytes may be seen in the lumen or intima (1 6, 1 9). By IF, variable staining for IgG, 1gM, IgA, complement components, and fibrin-related antigens is present in the wall and extends to the lumen, (1 6, 1 9,26) (Figure 8). Ultra- structurally, there is swelling or loss of endothelium, with massive confluent intraluminal and mural deposits of granular electron-dense material, with the combined appearance of insudated proteins, and immune deposits, sometimes associated with tactoids of fibrillar fibrin and platelets. Degenerative changes may be seen in the medial myocytes adjacent to these deposits (16). The pathogenesis of this noninflammatory necrotizing vascubopathy is uncertain. Its occurrence In patients with mild or no hypertension, the infrequent presence of hypertensive retinopathy, and the histopathologic findings of vascular immune deposits in Figure 5. Electron-dense deposit with organized substruc- addition to fibrin all militate against malignant hy- ture in the media of a small artery. Uncomplicated vascular pertension as the primary etiologic process. However, immune deposits. Electron micrograph, x15,000. it is likely that the superimposition of severe hypertension may exacerbate these vascular lesions Class ha, where mesangial deposits do not incite (19,26). The presence of abundant electron-dense gbomerular cell proliferation (20). vascular deposits consisting in part of immunoglob- This type of lupus vasculopathy must be differen- ulins and complement strongly suggests immuno- tiated from hyalinosis, a lesion frequently associated logic factors in the evolution of these lesions (18,26). with hypertension and the arteriobosclerosis that Secondary thrombosis might contribute to the dam- commonly accompanies the more chronic, inactive age occurring in those vessels (16,17,19). The fact forms of lupus nephritis. The associated findings of that such vascular lesions are most common in pa- intimal and medial sclerosis involving the arterioles tients with active proliferative lupus gbomerubone- and the small arteries and the presence of 1gM and phritis also supports a role for immune deposition as C3 only (but not of IgG and IgA) by fluorescence a primary process (16-19,26). The possible involve-

Journal of the American Society of Nephrology 1501 Renal Vascular Complications of SLE

Figure 6. Granular electron-dense deposits wIthIn the basement membrane between the medial myocytes of an Interlobuiar artery. Uncomplicated vascuiar immune deposits. Electron micrograph, x5,000.

ment of other recently described mechanisms of vascular injury, such as antiendothelial antibodies, activated monocytes and neutrophils, cytotoxic T cells, and lymphokine-mediated damage, remains to be defined (27). It is likely that the initial endothelial cell damage associated with immune deposition is followed by plasma protein insudation in vessel walls and subsequent Intravascular coagulation, possibly exacerbated by hypertension. The gbomerular lesion that most closely resembles this type of vasculopathy is focal segmental necrotizing glomerulonephritis (WHO Class III) (28).

ThrombotiC MiCroangiopathy This type of vasculopathy may involve the renal Figure 7. Nonlnflammatory necrotizing lupus vasculopathy affecting two arterioles from a patient with diffuse prolifer- vessels of lupus patients with TTP or antiphospho- ative lupus nephritls. The lumen Is occluded by eoslnophlilc lipid antibody syndrome or may occur without a rec- smudgy material with endotheilal denudation and pyknotic ognizable thrombotic systemic process. It Is often nuclear debris. Note the absence of leukocytes Infiltrating difficult to distinguish from the noninflammatory the vessel wali. Hematoxyiln and eosln, x320. necrotizing vascubopathy described above. It also

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Figure 8. An interlobular artery from the same patient as shown in Figure 7 shows staining of the intraluminal material with antisera to lgG (a) and fibrin-reiated antigens(b). The eiastica is disrupted. Noninflammatory necrotizing lupus vasculopathy. IF, x400.

Figure 9. Multiple thrombi occlude giomerular capillaries and arterioles. UP-like syndrome in SLE. Jones methenamine silver, x320. most commonly affects pregbomerular arterioles and small interlobular arteries. Unlike noninflammatory Figure 10. A large flbrin thrombus obstructs the afferent necrotizing vasculopathy, however, it also involves arteriole as it enters the glomerular tuft. UP-like syndrome the vascular pole and adjacent gbomerular capillaries In a patient with WHO Class IV lupus nephritis. Jones methe- (22,29-3 1) (Figures 9 and 10). Histologically, it namine silver, x320. appears identical to the vascular changes seen in nonlupus patients with hemolytic-uremic syn- tinguished from noninflammatory necrotizing vas- drome (HUS), TTP, malignant hypertension, sclero- cubopathy, however, by the predominance of fibrin derma, and other thrombotic microangiopathies and the absence of discrete immune deposits on IF (19,25,31,32). In the acute phase, there is marked and EM. Frequently, the media appears thinned and luminal narrowing or total occlusion by intraluminal, stretched around the expanded intima. There is no subendothelial, or medial accumulation of eoslno- leukocyte infiltration of the vessel wall. In the philic, fuchsinophilic material with staining proper- chronic phase, mucoid edema of the intima and/or ties of fibrin (Figure 11), invariably associated with the “onion skin” type of intimal fibroplasia may occur endothellal swelling, denudation, and sometimes (25) (Figure 12). fragmented and/or hemolyzed erythrocytes. It is dis- The pathogenesis of thrombotic microangiopathy

Journal of the American Society of Nephroiogy 1503 Renal Vascular Complications of SLE

True Renal VasCulitis This is by far the least frequent renal vascular lesion encountered in SLE. Its morphologic appearance is identical to that of microscopic PAN (19,20,25). This vascular lesion is so uncommon in SLE that some have questioned whether its presence does not represent overlap with PAN rather than a true manifestation of SLE. The vessels affected are usually small and medium-sized arteries, most commonly intralobular arteries. There is prominent inflammatory cell infiltration of the arterial wall by neutrophils and mononuclear leukocytes, affecting the vessel eccentrically or circumferentially. This mural Inflammation is accompanied in the acute phase by fibrinoid necrosis, usually most severe in the intima and to a lesser extent in the media (Figure 1 3). In some biopsies, rupture of the elastic lamellae is seen (2 1). IF discloses fibrin-related antigens sometimes associated with less intense staining for immunoglobulin and/or complement fractions. Al- Figure 11. An arteriole from the same patient as shown In though there are no EM reports of this lesion in SLE Figure 10 staIns posItively for fibrin. UP-like syndrome in a patients, the few EM descriptions of necrotizing vas- patient wIth WHO Class IV lupus nephritIs. Phosphotungstlc culitis of the PAN type in nonlupus patients have acid hematoxylIn, x320. disclosed no electron-dense deposits of the immune type, although fibrin deposition is common (34). Thus, the IF positivity may represent nonspecific trapping of circulating plasma proteins in the dam- aged arterial wall (35). However, ultrastructural studies are needed to conclusively exclude a role for immune deposits in the pathogenesis of these lesions in the setting of SLE. The pathogenesis of this rare, true inflammatory vasculitis resembling periarteritis nodosa may involve mechanisms similar to those proposed for vasculitides of the PAN type (35). The fact that intra-

Figure 12. Mucold edema of the Intima of an Interiobuiar artery (UP-like syndrome In SLE). Phosphotungstlc acid he- matoxylln, x320. in SLE is probably unrelated to immune complex deposition. In lupus patients with these findings on renal biopsy, accelerated hypertension, overlap with seleroderma, ‘FTP-like syndrome, or lupus anticoagulant syndrome should be excluded as possible etiologic factors (vide infra). Sometimes these vascular lesions are identified in the kidneys of patients without a clinically evident thrombotic tendency. The possibility of cyclosporin A nephrotoxlcity should Figure 13. Necrotizlng arteritis of the PAN type affecting an also be excluded in patients who have received this interiobular artery In a patient with diffuse proliferatIve lupus therapy for lupus nephritis because this medication nephrItIs. There is concentric inflammation of the vessel has been reported to cause a thrombotic microangio- wall. The endotheilum is focally denuded with fibrinold ne- pathy in organ allograft recipients (33). crosis of the intima. Hematoxylin and eosln, xlOO.

1504 Volume 4’ Number 8’ 1994 Appel et al

mural immune deposits have not yet been found in sociated with abrupt deterioration in the clinical these lesions and that they may occur in association course and an ominous prognosis. In another series with the benign mesangial pattern of lupus nephritis of five patients with a similar renal vasculopathy, makes a role for immune complex deposition unlikely serum creatinine values ranged from 0.8 to 1 .7 mg/ (20). To date, not enough of these cases have been dL and proteinuria ranged from 0.8 to 10 g daily, studied to determine whether circulating antineutro- exceeding 3 g in four patients (16). Hypertension was phil cytoplasmic antibodies may play a role (36). present in four of the five patients, but no blood Some of these cases are associated with systemic pressure exceeded 180/1 10 mm Hg. The pattern of vasculitis, whereas others appear to be limited to the lupus nephritis was diffuse proliferative glomerulo- kidney (personal observation). nephritis in four patients and mesangial proliferative glomerulonephritis in one patient. In the short period of follow-up, only one patient died with renal failure; EPIDEMIOLOGIC CLINICAL FEATURES, AND this patient also had cardiac and pulmonary disease. PROGNOSIS In that series, the authors could not distinguish such There are little data regarding the incidence of patients clinically from patients without renal vas- vascular lesions in lupus patients, their clinical cor- cular lesions. In a review of 1 7 cases of “angiitis” relates, and their potential reversibility with specific involving arterioles and interlobular arteries in SLE therapy. Major reviews on vasculitis and on renal patients (1 8), all patients had underlying diffuse pro- pathology in SLE make little reference to this Issue liferative lupus glomerulonephritis. Nephrotic-range (37,38). An analysis of the literature on this subject proteinuria was recorded in 50% of these cases. All is also made difficult by the failure of many authors of the following were more common in patients with to distinguish between the various types of vascular “angiitis” than in patients without these vascular lesions outlined above. lesions: hematuria, urinary casts, increases in the Tsumagari et at. described “vasculitic” lesions in serum creatinine level, hypertension, active serology, 1 6 of 1 00 autopsied SLE patients and other renal and a progressive course to renal failure and/or vascular lesions in 1 7 of 80 patients (25). In one death. series of 88 biopsied SLE patients, Baldwin et al. In a series of 100 autopsy cases, four of the seven described 9 patients with necrotizing fibrinoid vas- patients with “necrotizing arteritis” had accelerated culopathy (26). Recently, a cooperative study of vas- hypertension (diastolic blood pressure, >130 mm Hg) cular lesions in 285 lupus nephritis patients from 20 and two others were hypertensive; six of the seven Italian centers found lupus vasculopathy in 27 pa- developed renal failure, with four of these six having tients (9.5%) and arteriosclerotic lesions in 20 (7.0%) a rapid progression to uremia (25). Lesions described (21). Another study found a much higher incidence as “mucinous intimal thickening” were found in nine of renal vascular lesions In autopsy material from cases and were associated with hypertension in SLE patients (7 of 20) compared with renal biopsies seven of these (accelerated hypertension in three). (10 of 200), a discrepancy probably related to sample Nephrotic syndrome was present in only three of size, severity and/or duration of SLE, and differences these patients, all of whom eventually developed in treatment (1 7, 1 9). The majority of SLE patients renal failure. The third vascular lesion described by with renal vascular lesions have been young women, this group, “onion skinning” of the intima, was iden- with only one study suggesting a higher frequency of tified in two patients, one of whom had hypertension such lesions in men (19). and one of whom developed renal failure. Grishman The clinical features associated with renal lupus et al. noted acute “arteritis” much more commonly In vasculopathy, defined as fibrinoid necrosis without their autopsy cases (7 of 20) than in their biopsy true inflammation of the vessel wall, are described cases (1 0 of 200), suggesting that It carries a worse in a few series of SLE patients. Most authors agree prognosis (17). In a subsequent study of the vascular that this lesion adversely affects outcome. In one lesions in lupus nephritis, Grishman and Venkata- series, acute severe glomerulonephritis associated seshan noted arterial lesions in the autopsy speci- with the onset of severe hypertension and a rapid mens of 8 of 24 patients who died in the presteroid progression to renal failure was present in eight of era and in 5 of 26 who died in the “modem” era (19). nine patients with lupus vasculopathy (26). Most of These lesions were again identified less frequently in these patients had plasma creatinine values of less renal biopsy specimens (19 of 276 patients). Most than 2 mg/dL when they developed a deterioration in patients with vascular lesions had diffuse prolifera- their course. Six progressed to renal failure in fewer tive lupus glomerulonephritis, hypertension, and a than 6 weeks, and the others did so In 4 to 14 months. progressive course to renal failure. Likewise, a recent All patients had hypertension and congestive heart Italian study found over half of their lupus vasculo- failure, with severe retinopathy present in five of the pathy patients to have diffuse proliferative lupus, nine. Thus, this type of renal vasculopathy was as- and an elevated creatinine and hypertension were

Journal of the American Society of Nephroiogy 1505 Renal Vascular Complications of SLE

more common in that group than in patients without experience with lupus nephritis have only rarely seen renal vascular changes (21). inflammatory vasculitic lesions resembling PAN in The presence of uncomplicated immune complex SLE biopsies or autopsies (personal communication). deposits in the walls of small renal arteries without This form of vasculitis was observed by Appel et al. inflammation or necrosis is quite common in lupus in only 1 (1.8%) of 56, by Grishman et al. in only 1 nephritis, especially in WHO Classes III and N. These (0.3%) of 326 (19,20), and by Banfi et al. in only 8 deposits are focally distributed, and although not well (2.8%) of 285 cases (21). In the Italian study (21), studied, they do not appear to affect significantly the many of the patients also had marked elevation of clinical course and prognosis. their serum creatinines and two thirds had hyperten- Among the renal vascular lesions occurring in SLE, sion. In that study, patients with lupus vasculopathy true inflammatory vasculitis is the least common. A or true vasculitis (5-yr renal survivals, 68 and 80%) number of experienced nephrologists with extensive had a less favorable renal survival than did lupus nephritis patients without vascular lesions (5-yr renal survival, 90%) (21). Thus, although some fea- TABLE I . Renal Vascular Lesions in SLE tures vary from series to series, in general, SLE pa- Morphologic Categories tients with renal vascular lesions are likely to have Uncomplicated vascular immune deposits underlying proliferative glomerular lesions, hyper- Nonlnflammotory necrotizing vasculopathy tension, and renal insufficiency. Many have a pro- Thrombotlc microanglopathy gresslve course to renal failure and a worse survival True renal vascuiltls than do patients without vascular lesions. Clinical Thrombotic Syndromes UP Antiphospholipld antibody syndrome THERAPY RVT Precise therapy for the renal “vasculopathic” lesions of SLE remains undefined. For some of the

TABLE 2. Pathology of renal vascular lesions in SLED

Vessels involved Vessel Mural Arteries Arterioles Veins Deposits Necrosis Inflammation

Uncomplicated Vascular Im- ++ + + igG, 1gM, IgA, C3, C1 0 0 mune Deposits Noninfiammatory Necrotizing + ++ 0 IgG, 1gM, igA, C3, C1 + 0 Vasculopathy FRA Thrombotic Microanglopathy + ++ 0 FRA + 0 True Renal Vasculltis ++ + 0 FRA ++ ++

++. FRA. fibrin-related antigens; 0. 4+ semiquantitative grading scale.

TABLE 3. ClinIcal features of renal vasculopathies in SLE#{176}

Frequency WHO Class Hypertension Prognosis Insuncy

Histopathologic Lesion Uncomplicated vascular Immune ++++ All, Mostly iii, IV 0 0 Good deposits Noninflammatory necrotizing ++ Mostly IV + + Poor vasculopathy Thrombotic microangiopathy + All + + Variable True renal vasculitls 0/+ All + + Poor Clinical Syndromes UP + All + + Variable AntiphospholIpid syndrome ++ All + + Variable Renal vein thrombosis ++ V 0 + Good

See footnote to Table 2.

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renal vascular lesions that carry a poor prognosis diagnostic laboratory tests. Despite some overlap of aggressive methods of treatment appear to be justi- symptoms between these two distinct entities, both fled. If immune deposition underlies their pathogen- diseases have been well documented to occur simul- esis, then methods that will reduce the formation taneously in a small number of patients. The inter- and deposition of immune complexes such as corti- relationship of SLE, an immunologic disease, and costeroids, cytotoxic drugs, and perhaps plasmapher- ‘FTP, a disease of coagulation, raises intriguing ques- esis may be rational. Likewise, control of blood pres- tions about their pathogenesis. Recent studies on sure is reasonable, regardless of the magnitude of its SLE patients with antiphospholipid antibodies may contribution to the pathogenesis of the various renal help elucidate the basis of this interrelationship. lesions. In some patients, all of these measures have The true incidence of a TTP-like syndrome in SLE been tried but with limited evidence of benefit. Al- patients is unknown because of the varying criteria though antiplatelet or anticoagulant therapy may for the diagnosis of T’FP and SLE in different centers have a role in some patients with prominent micro- in the past. Levine and Shearn found evidence of SLE thrombosis, proof of their efficacy is also lacking. In in 23% of 1 5 1 cases of T’FP (46). That study, however, addition, the potential risks of anticoagulation are was based solely on clinical features, a positive LE increased in this hypertensive population. Indeed, it prep, and postmortem pathologic findings. In another is unclear whether the noninflammatory necrotizing study, 1 3 of 27 1 patients with ‘FTP had tlinical find- vasculopathy requires any treatment other than con- ings suggestive of SLE and 7 had positive LE preps trol of the hypertension and standard management (47). Other cases in the older literature have also for the immunologic disease process. Cases of true failed to document adequately the coexistence of arteritis would be best treated as a renal vasculitis, these two disease processes (46,48-5 1). Rothfield and most clinicians would opt for cytotoxic therapy noted the association of ‘FTP and SLE in only 2 of with or without corticosteroids (35). 433 patients with SLE (52). Thus, only a small num- Even in early studies, renal arterial necrotizing ber of SLE patients have experienced the full pentad lesions were listed among the active lesions of lupus of ‘FTP-like symptoms (22,31 ,34). On the other hand, nephritis, i.e., those lesions that should be consid- glomerular microthrombi resembling those of TTP ered progressive unless adequately treated (39). Al- were found in 35 of 1 03 SLE renal biopsies, occa- though some later studies included necrotizing angi- sionally in association with profound thrombocyto- itis in a renal histologic activity index (40), more penia (53). Although those patients would hardly recent formulations of histologic activity indices of qualify as having true ‘FTP, it is certainly possible lupus nephritis used for prognostic considerations that they have a kidney-limited form of the disease have not included vascular lesions (41). Investigators process. Likewise, some patients with lupus “vascu- now recognize that the presence in lupus nephritis litis” share many renal histopathologic findings with of arteriopathies characterized by necrosis, throm- rrP (16). Other workers have also noted a clinical bosis, and/or inflammation is often associated with picture resembling TTP or HUS in their SLE patients the most severe forms of glomerulonephritis and a with vasculopathic lesions (1 7- 1 9). A recent Italian significantly worse prognosis. It should be noted that collaborative study found 8% of lupus nephritis pa- the involvement of the small renal arteries also con- tients to have HUS/TTP-like lesions (21). Many if not fers a worse prognosis in other glomerular diseases most of the above studies lack data on the presence such as IgA nephropathy and HUS (42-44). of anticardiolipin or other antiphospholipid antibodies (vide infra). The clinical features of ‘FTP are those of a multi- THROMBOTIC SYNDROMES IN SLE system disease due to the microthrombotic occlusion Three thrombotic vascular syndromes can be as- of small vessels in many organs (45). The diagnosis sociated with SLE: a TTP-like syndrome, the anti- of SLE may precede, be concurrent with, or follow phospholipid syndrome, and RVT. Because of their the diagnosis of T’FP (22,29-31,48,49,54,55). SLE relative frequency and complex pathogenesis, these may be either clinically and serologically active or syndromes are discussed separately below. inactive at the onset of active TTP (22,29-31,54,55). In SLE patients, symptoms related to the T’TP-like syndrome have included fever, malaise, petechial UP Syndrome and purpuric skin lesions, abdominal pain and ten- TTP is a syndrome characterized by the pentad of derness, jaundice, and gastrointestinal bleeding (29- fever, thrombocytopenia, microangiopathic hemo- 31,55). Neurologic involvement has included head- lytic anemia, fluctuating neurologic symptoms, and ache, reduced consciousness, disorientation, com- renal involvement (45). TTP shares many features bativeness, seizures, transient pareses, nerve pal- with SLE, and the two diseases were commonly mis- sies, and coma. Renal involvement by the ‘FTP-like taken for each other before the advent of accurate process has ranged from asymptomatlc urinary find-

Journal of the American Society of Nephroiogy 1507 Renal Vascular Complications of SLE

ings, to mild reduction In the GFR, to acute renal Most of these changes are similar to those found in failure requiring dialysis (30,31 ,55). Hypertension patients with TTP or HUS without SLE. The patho- has been mild or absent in the majority of cases physiology of idiopathic ‘FTP remains unclear. Pos- (29,31 ,48,49,55). However, in one study of 24 cases sible inciting etiologic factors have included infec- of HUS/TTP-like syndrome in lupus nephritis, there tion, abnormal endothelial function, genetic predis- was a marked elevation of the mean serum creati- position, and autoimmune disease (45). Virtually all nine, proteinuria averaged 3 g daily, and over 90% of theories, however, suggest a key role for vascular the patients were hypertensive (21). Most well-docu- endothelial damage and microthrombosis. The pres- mented cases have had clear evidence of the microan- ence of abnormal platelet aggregating factors and the giopathic process on examination of peripheral blood deficiency of factors that prevent coagulation smears, and the thrombocytopenia Is usually pro- have been documented in some patients with ‘FTP found, often less than 20,000/mm3. Other coagula- (45,56,57). Defective processing of very large Factor tion studies have been normal (prothrombin time, VIII:vWF multimers after secretion by endothelial partial thromboplastin time, fibrin degradation prod- cells, lack of a prostacyclin releasing factor, and ucts), excluding a diagnosis of disseminated intra- deficiency of an immunoglobulin that inactivates vascular coagulation. Although some patients have platelet aggregation have all been identified in at been shown to have altered coagulation studies be- least some patients with ‘FTP. The pathogenesis of cause of the presence of the lupus circulating anti- ‘FTP-like syndromes in the setting of SLE is no less coagulant (22), the lupus anticoagulant is absent in obscure. Although a primary immunologic stimulus most patients (31). for the initiation of vascular endothelial damage is Only a limited number of studies have described an attractive hypothesis, some patients have been the histopathology of ‘FTP-like lesions in patients serologically inactive at the onset of their ‘FTP. More- with well-documented SLE. Oen et al. described the over, the rarity of this occurrence in the vast majority course of a 1 7-year-old girl with SLE and ‘FTP whose of patients with very active SLE makes the theory of renal biopsy showed glomerular changes of SLE but a nonspecific immunologic stimulus less likely. Con- also marked congestion of the glomeruli and occlu- ceivably, the onset of microthrombosis in the glomer- sion of some glomerular capillaries by fibrin thrombi ular capillaries (53) might trigger more widespread (29). Cecere et at. described abundant microthrombi systemic thromboses. However, the low incidence of in the arterioles and capillaries of the kidneys, as T’FP relative to the frequent histologic detection of well as in many other organs at autopsy (30). Magil glomerular capillary microthrombi in patients with et at. described a case with underlying diffuse prolif- active SLE nephritis argues against this mechanism erative lupus glomerulonephritis with arterlolar (53). The lupus circulating anticoagulant has been thromboses and intimal proliferative changes, nar- documented in rare cases of the ‘FTP-like syndrome rowing the lumen of the interlobular arteries and in SLE patients (22), but the majority of patients lack arterioles (22). On EM, the glomeruli showed not only this abnormal immunoglobulin. Moreover, many pa- scattered subendothelial and mesangial deposits, but tients with high-titer antiphospholipid antibodies also widening of the subendothellal space by elec- (whether anticardiolipin or lupus anticoagulant) will tron-lucent flocculent and fibrillar material. Gelfand have elevated activated partial thromboplastin times, et at. found one of their patients to have only mes- which are normal in ‘FTP. Because SLE patients with angial sclerosis without proliferative or necrotizing ‘FTP appear to respond to the same therapeutic ma- glomerular features; however, the small arteries and neuvers as patients with idiopathic ‘FTP (vide infra), arterioles showed fibromucoid thickening of the in- it is likely that once the initiating mechanism has tima and recent thrombi extending into the glomer- been triggered the subsequent events leading to ml- ular capillaries (31). These thrombi stained positive crothromboses are similar in the two populations. for fibrin by both the phosphotungstic acid hematox- The 5-yr renal survival of lupus nephritis patients ylin and picro-Mallory (Lendrum) stains. The second with HUS/TTP-like lesions has been shown to be less patient described by those authors had a renal biopsy favorable than that of lupus nephritis patients with- performed when the TTP was inactive. The biopsy out renal vascular changes (21,45). Until recently, showed no recent thrombi, but the small arteries and therapy for idiopathic ‘FTP has included treatment arterioles displayed severe fibromuscular thickening with steroids, antiplatelet agents, heparin, and sple- of the intima. Banfi et at. described intimal prolifer- nectomy in some cases (45). These forms of treatment ative changes with mucoid edema and luminal nar- were often associated with a high mortality rate. rowing in the interlobular arteries and arterioles, as Recently, the use of plasma exchange and plasma well as arteriolar thrombosis, in their 24 patients. In infusion therapy has been associated with markedly 15 of these patients, glomeruli showed ischemic improved survival (58,59). It is unclear whether such changes, and in 10, glomerular thrombi were ob- improved survival is related to current therapeutic served (21). interventions or to better supportive care (45). In rare

1508 Volume 4’ Number 8’ 1994 Appel et al

patients with SLE and the ‘FTP-like syndrome, the thelial injury and necrosis are also common in active use of heparin and antiplatelet agents has been suc- forms of lupus nephritis not associated with these cessful (55). Plasma infusion and/or exchange ther- antibodies (53). apy have likewise resulted in dramatic benefits in In a review of over 1 00 biopsied SLE patients, Kant anecdotal reports (29,31). Such treatment has re- et at. found glomerular capillary thrombosis in 34 sulted in the resolution of profound neurologic biopsies (53). Although only 7 patients had an iden- depression and the reversal of renal failure requiring tifiable lupus anticoagulant, 3 1 patients had active dialysis (31). The exact nature, quantity, and fre- proliferative lupus nephritis (WHO Class III or N). quency of the plasma product to be infused are not Subsequent studies by that group of investigators well defined, and controlled trials are lacking. Sero- documented the presence of renal thromboses in 14 logic SLE abnormalities should also be corrected with of 1 8 SLE patients with the circulating lupus anti- steroids and/or cytotoxic agents, whereas plasma in- coagulant (68,69). Recent studies of lupus patients fusion therapy Is directed at the T’FP-llke lesions. have confirmed the association between mntraglomer- The role of plasma exchange and plasmapheresis ular thrombi and serum IgG antiphospholipid anti- versus that of isolated plasma infusion is unsettled. bodies (70,71). In one series of 33 SLE patients with It appears that the latter is equally effective if renal the lupus anticoagulant, 5 had histologic evidence of function is adequate to prevent volume overload. renal thrombotic microangiopathy (70). That study found no correlation between the presence of the microangiopathy and the class of lupus nephritis, Antiphospholipid Antibody Syndrome hypertension, protemnu na, or renal function (70). Many patients with SLE produce autoantibodies Some studies indicate a worse prognosis in SLE pa- against certain phospholipids. These autoantibodies tients with the circulating lupus anticoagulant and may be detected by assays against the phospholipid renal biopsy documentation of thrombotic microan- cardiolipin (anticardiolipin antibodies), by interfer- giopathy (70). However, in a recent study of 76 pa- ence with coagulation assays (the lupus anticoagu- tients with lupus nephrltis, although the presence of lant, which interferes with the phospholipid compo- IgG antiphospholipid antibodies was associated with nent of the prothrombin activator complex), by blo- glomerular thrombi, there was no correlation with logic false-positive tests for syphilis (false-positive renal histologic pattern or long-term renal function VDRL), or by other specific assays measuring anti- (71). phospholipid antibodies (ELISA) (60-64). In a review By contrast, some patients with antiphospholipid of data from 2 1 studies on the prevalence of the lupus antibodies appear to have a severe form of thrombotic

anticoagulant in SLE patients, 34% of all 1 , 1 1 1 pa- microangiopathy, which dominates their clinical tients were found to have this antibody and 28% of presentation. Kincaid-Smith et at. described the over 500 unselected SLE patients in consecutive se- renal biopsies of a group of 1 2 patients with the ries had the antibody (63). In that review, 44% of 815 circulating lupus anticoagulant. Four of the 1 2 had SLE patients had anticardiolipin antibodies as did evidence of SLE (67). The four patients were hyper- 42% of almost 500 unselected patients in consecutive tensive (two with malignant levels of hypertension) series. The name lupus anticoagulant is a misnomer, and thrombocytopenic, and all had renal insuffi- because most patients with antiphospholipid anti- ciency. Renal biopsy revealed diffuse proliferative bodies are predisposed to thrombotic events rather lupus nephritis in two patients and mild mesangial than to bleeding. These patients will have a high lesions in the other two. Regardless of the WHO Class incidence of arterial and venous thromboses, spon- of renal involvement, all had fibrin thrombi in the taneous abortions, neurologic disorders, and throm- glomeruli, arterioles, and intralobular arteries. On bocytopenia (6 1-64). A high titer of IgG anticardio- repeat histologic evaluation in two cases, the inter- 11pm antibody by ELISA has been correlated in some lobular arteries showed fibrosis as well as cellular studies with a greater tendency to thrombotic events. intimal proliferation. D’Agati et at. described two However, neither the titer of antiphospholipid anti- SLE patients as part of a series of three patients with bodies nor the frequency of thrombotic events cor- anticardiolipmn antibodies and glomerular throm- relate well with either SLE clinical or serologic activ- boses (65). Although the clinical features were varied, ity (61,62). Although SLE patients with antiphospho- including asymptomatic proteinuria, the nephrotic lipid antibodies may have thromboses of large renal syndrome, renal insufficiency, and hypertension, vessels, microthrombi of glomerular capillaries no patient had active SLE. Biopsies again showed have now been well documented in several series thrombi in the glomeruli, arterioles, and interlobular (22,53,65-67). The role of antiphospholipid antibody arteries, but no active endocapillary proliferative lu- has been more difficult to establish in glomerular pus nephritis (Figure 14). Others have shown similar capillary thrombosis than in large-vessel thrombosis thrombotic and ischemic changes in small series of because glomerular lesions characterized by endo- patients with SLE (72).

Journal of the American Society of Nephrology 1509 Renal Vascular Complications of SLE

The exact Incidence of RVT in SLE patients is unknown. It has occurred in both males and females of all ages. Its predominance in young women reflects the higher prevalence of SLE in this population. Cer- tam SLE patients with the nephrotic syndrome, prior episodes of thrombophiebitis, and antiphospholipid antibodies have a higher incidence of RVT. The association of RVT, the nephrotic syndrome, and SLE was first emphasized in 1976 (74). As in other renal diseases, RVT in SLE appears to be a complication rather than a cause of the nephrotic syndrome. Gil- sanz et at. prospectively searched for RVT by angiog- raphy in 20 SLE patients (79). RVT was detected in 2 of 6 patients with the nephrotic syndrome, but in only 1 of 14 without the nephrotic syndrome. Llach Figure 14. Organizing recanaiized thrombus of an interiob- et at. prospectively studied 48 nephrotic patients for ular artery in a patient with membranous lupus nephntis the development of RVT (88). Although 1 1 nonlupus and high levels of anticardiolipin antibody. The patient also patients with either idiopathic membranous or mem- had Ilvedo reticularis, cardiac murmur, and multi-infarct branoproliferative glomerulonephritis were docu- dementia. Hematoxylin and eosln, x250. mented to have RVT, none of the 5 nephrotic lupus patients had RVT. The renal biopsy findings in these The mechanism of the procoagulant effect of anti- patients were not described. In a retrospective review phospholipid antibodies is still unclear (61,62,64,65). of 280 patients with either idiopathic membranous Because the microthromboses may occur in patients nephropathy or lupus nephritis who had undergone without evidence of active vascular or glomerular renal biopsy, 1 1 were found to have RVT, including immune deposits, mechanisms other than immune 3 patients with SLE (77). In that retrospective study, complex-related injury must be involved. It has been the exact number of SLE patients studied and the suggested that the autoantibody may initiate endo- number of SLE patients in which venography-an- thelial damage by binding to the endothelial or plate- giography was performed are not indicated. In a re- let plasmalemmal phospholipid. Decreased endothe- cent prospective study, 27% of nephrotic SLE pa- hal release of prostacyclmn and enhanced platelet tients had RVT in contrast to none of the non-ne- aggregation have been proposed. phrotic SLE control population (80). Unfortunately, Regardless of the mechanism of damage, there is many of these studies fail to indicate the histologic little doubt that coagulation within the vessels is pattern of lupus nephritis. Most biopsied nephrotic central to the disease process and this is the rationale lupus patients with documented RVT have had a for anticoagulation therapy consisting of heparin fol- membranous pattern of lupus nephritis (WHO Class lowed by coumadin. Most investigators feel that all V). The incidence of RVT in nephrotic SLE patients patients who have experienced any clinically signif- with proliferative patterns of lupus nephritis is much icant thrombotic event should be “anticoagulated” for lower (74). as long as the autoantibody persists. Likewise, those Other factors often associated with RVT in SLE patients with renal biopsy findings of glomerular or patients include a prior history of thrombophlebitis arterial thrombosis should be anticoagulated in a and the presence of anticardiolipin antibodies or the similar fashion. Attempts to decrease the titer of the lupus circulating anticoagulant. In a prospective antiphospholipid antibody by immunosuppressive study, 8 of 13 SLE patients with a history of prior agents have generally been disappointing. Despite thrombophlebitis had RVT, whereas none of 20 SLE the remission of clinical and serologic activity, most patients without previous thromboses had RVT (80). patients have persistence of the antiphospholipid an- Although there was no higher incidence of the cir- tibody (65; personal observation). Whether plasma- culating lupus anticoagulant in this population, other pheresis may have an adjunctive role is still un- studies have noted an association between this ab- known, but there are reports of improved renal func- normal immunoglobulin and venous thrombotic tion after plasma exchange in this population (66,67). events (60). However, most studies that report high incidences of thrombotic episodes in SLE patients do not indicate a correspondingly high incidence of clin- Renal Vein Thrombosis ically evident RVT (2,89). In a recent study of 35 Since the first report of renal vein thrombosis patients with a circulating anticoagulant, 8 of whom (RVT) in a lupus patient in 1968 (73), this complica- had clinically significant thrombotic episodes, no pa- tion has been reported in over 40 cases (1,60,74-87). tient experienced RVT (89). Thus, thrombophlebitis

1510 Volume 4’ Number 8 #{149}1994 Appel et al

and circulating anticoagulant are much less impor- velopment of an extensive collateral circulation is tant than the nephrotic syndrome as predisposing usually not found and renal infarction may occur factors to RVT in SLE. (75,78). The clinical presentation of RVT in SLE patients The renal histopathology in SLE patients with RVT does not differ from that of RVT in nephrotic patients reflects both the nature of the underlying histologic without SLE. Most patients have the onset of the pattern of SLE and the chronicity of the RVT. Many nephrotic syndrome with heavy proteinuria and hy- SLE patients with the nephrotic syndrome and RVT poalbuminemia before the onset of RVT. Systemic have not had a renal biopsy at the time of diagnosis disease activity has been variable, but because most of the RVT (79,80,84). The vast majority of those have membranous lupus glomerulopathy, serologic biopsied have the membranous pattern of lupus tests are often less active (74). Indeed, some patients nephropathy (WHO Class V) (74,75,77,78,82). Al- with the nephrotic syndrome and apparently “mdi- though occasional patients have been observed with opathic” membranous nephropathy, with or without mesangial or proliferative lesions (WHO Class II, III, associated RVT, years later developed signs and or N) (25,60,81), some of these lacked IF and EM symptoms of active SLE (75,77). In such patients, studies necessary to exclude a membranous compo- renal biopsy findings of ( 1 ) mesangial, subendothe- nent (25,60,73,85). In patients with relatively acute hal, or tubulointerstitial electron-dense deposits, as- RVT, interstitial edema, tubular degeneration, and sociated with the dominant epimembranous glomer- margination of polymorphonuclear leukocytes in the ular deposits and (2) endothelial tubuloreticular in- glomerular and interstitial capillaries have been clusions and/or (3) IF findings of glomerular deposits noted (74). Rarely, thrombi are observed in the gb- of IgA and Clq (as well as IgG and C3) may have merubar capillaries and in the small, intrarenal ye- predictive value in identifying those individuals with nous radicals (75) (Figure 1 5). No inflammatory membranous glomerulopathy who will later develop changes are present in and around the wall of the SLE (90). thrombosed renal veins. With more chronic RVT, The clinical presentation of acute RVT may include findings include interstitial fibrosis and tubular atro- flank pain, costovertebral angle tenderness, and phy out of proportion to the glomerular changes gross hematuria (74,75,78,80). However, when RVT (73,74,81 ,85). These findings in a patient with mem- is more indolent, the patient may be asymptomatic branous gbomerubopathy, with or without evidence of without urinary sediment changes or increased pro- SLE, should prompt a search for associated RVT. teinuria to suggest the diagnosis of RVT (74). In SLE The pathogenesis of RVT in SLE is not completely patients, the first manifestations of RVT or inferior understood. SLE itself is associated with an in- vena cava thrombosis may be the symptoms of short- creased incidence of venous thromboses and throm- ness of breath, dyspnea, and tachypnea associated bophlebitis. In one series of 1 1 4 patients fulfilling with pulmonary emboli (74,78). These symptoms are the American Rheumatism Association criteria for easily mistaken for lupus pleuritis or infectious pneu- SLE, over 1 2% had episodes of thrombophlebitis (84). monia. Oliguria has rarely been noted in the SLE Other series have reported a 5 to 1 5% incidence of patients with RVT, and usually, there is no signifi- venous thrombosis in SLE (1 ,82). The cause of these cant reduction in the GFR (74). Unilateral renal en- thrombotic events is unclear, but hypotheses have largement, ureteral notching due to engorged collat- included “slow intravascular coagulation,” possibly erals, and pyelocalyceal abnormalities have been ob- related to the hypercoagulable state of the nephrotic served on the iv urogram in some patients (74,75,77). syndrome, small vessel vascubitis, or venulitis (an Other patients have had entirely normal iv urograms hypothesis not well supported by histologic findings), despite documented RVT on venography (74,77). In and the presence of antiphospholipid antthodies and most cases, renal venography has firmly established other circulating factors promoting coagulation. The the diagnosis by demonstrating a filling defect in the lupus “anticoagulant” paradoxically promotes throm- renal vein, often extending into the inferior vena bosis rather than causing a bleeding tendency (vide cava. Moreover, the usual washout or “streamer” ef- supra), and thromboembolism in patients with fect of unopacified blood from the renal vein is not antiphospholipid antibodies is well documented seen in patients with RVT (73,74). The use of Doppler (60,89,91). ultrasonography and magnetic nuclear resonance Clearly, the general occurrence of extrarenal ve- imaging in the diagnosis of RVT appears promising, nous thromboses in SLE cannot account for the high but the incidence of both false-negative and false- frequency of RVT in SLE patients with the nephrotic positive results remains to be defined. Chronic RVT syndrome. RVT is clearly a consequence rather than may be associated with extensive venous collateral a cause of the nephrotic syndrome in the vast major- circulation, especially on the left side (because of the ity of cases. The nephrotic syndrome itself is associ- origin of the left gonadal and adrenal veins from the ated with a hypercoagubable state. Factors favoring left renal vein) (81). In complete right RVT, the de- coagulation in nephrotic patients include increased

Journal of the American Society of Nephrology 1511 Renal Vascular Complications of SLE

Figure 15. An organizing thrombus (arrows) is present within an interiobular vein from a patient with diffuse proliferative and membranous lupus nephrltIs. (WHO Classes IV and V) complicated by RVT. Hematoxylin and eosin, x80. levels of Factors V and VIII, fibrinogen. and fl-throm- that patients with recurrent RVT and those with bogbobulmn; reduced levels of the inhibitor of coagu- persistent severe hypoalbuminemia due to their ne- lation antithrombin III; defects in the fibrinolytic phrotic syndrome should be maintained on long-term system; thrombocytosis and increased platelet a.ggre- or permanent anticoagulation therapy. gation (92). Some inhibitory factors such as antithrombin III are lost in the urine in the nephrotic ACKNOWLEDGMENTS state. Thus, the postglomerular circulation and the The authors thank Dr. Alice Appel for her editorial assistance. Mr. renal veins would be expected to have particularly Al Lamme for photography assistance, and Mr. Liewelyn Ward for low levels of this protein relative to the systemic technical assistance. venous blood, thereby predisposing to coagulation at this site. The chronic nonselective protemnuria in REFERENCES those gbomerular diseases most frequently associated 1 . Wallace DJ: Differential diagnosis and disease with RVT (idiopathic membranous and idiopathic associations. In: Wallace DJ, Hannahs Hahn B, membranoproliferative glomerubonephritis) would Eds. Dubois’ Lupus Erythematosus. 4th Ed. Phil- favor such a process. adelphia: Lea and Febiger; 1993:473-484. The course of patients with SLE, the nephrotic 2. Asherson PA, Derksen R, Harris EN, et a!.: syndrome, and RVT has been similar to that of pa- Large vessel occlusion and gangrene in systemic lupus erythematosus and “[upus-like” disease. J tients with idiopathic membranous nephropathy and Rheumatol 1 986; 134:740-747. RVT. Some patients have had life-threatening pul- 3. Babow J: Renal vasculitis. Kidney Int 1985;27: monary emboli (74); others have remained asympto- 954-964. matic. In general, those with total occlusion of the 4. Adelman DC, Saltiel E, Klnenberg JR: The neu- ropsychiatric manifestations of systemic lupus right renal vein have suffered a reduction in GFR erythematosus: An overview. Semin Arthritis and, rarely, renal infarction. Those with partial oc- Rheum 1986; 15:185-199. clusion, especially of the left renal vein, often have 5. Newbold KM, Allum WH, Downing R, Symmons had no decrease in renal function. DPM, Gates GD: Vasculitis of the gall bladder in Thrombectomy in a limited number of patients has rheumatoid arthritis and systemic lupus cry- thematosus. Cbin Rheumatol 1 987;6:287-289. given equivocal results at best (75). Anticoagulation 6. Sanders E, Hogenhuis LA!!: Cerebral vasculitis with heparin followed by long-term oral anticoagu- as presenting symptom of systemic lupus lation with coumadin for 4 to 6 months has been erythematosus. Acta Neurol Scand 1986;74: rewarding (74,86). Adequate anticoagulation has led 75-77. to recanalization of the renal vein and reduced pul- 7. Kaufman JL, Bancilla E, Slade J: Lupus vasculitis with tibial artery thrombosis and gan- monary embolic complications (74). Other patients grene. Arthritis Rheum 1986;29:1291-1292. have been treated successfully with streptokinase as 8. Hochberg MC, Boyd RE, Ahearn JM, et a!.: well as heparin (60). Some investigators advocate Systemic lupus erythematosus. A review of

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