Mary-Carmen Amigo and Romeo García-Torres
Even though the kidney is a major target organ in antiphospholipid syndrome (APS), until recently the renal manifestations associated with antiphospholipid antibodies (aPL) have received scarce attention. This can be explained because APS was first described in patients with systemic lupus erythematosus (SLE) and such research studies were focused on the immune-complex–mediated glomerulonephri- tis rather than renal vascular lesions that could be secondary. In addition, because of the frequent occurrence of thrombocytopenia and systemic hypertension, renal biopsy in APS patients would often be considered a high-risk procedure to be dis- couraged if not formally contraindicated [1].
Nevertheless, knowledge about renal vascular involvement in APS has slowly acquired a critical mass and it is now clear that large vessels, both arterial and venous, as well as the intraparenchymatous arteries and microvasculature may all be affected, with the clinical consequences shown in Table 9.1.
Renal Artery Lesions
Large- and medium-size vessel occlusion has been associated with APS in the context of SLE as well as in its primary form [2, 3].
99 Table 9.1. Renal vascular involvement in antiphospholipid syndrome.
Vascular lesion Clinical consequences
Renal artery lesions: (trunk or main branches) Renovascular hypertension (severe) Thrombosis/occlusion/stenosis? Renal infarcts (silent, painful, hematuria) Glomerular capillary thrombosis leading to Increased likelihood of renal insufficiency glomerular sclerosis (studied mainly in SLE)
Renal thrombotic microangiopathy (glomerular Systemic hypertension (usually severe) capillaries, afferent arterioles, and interlobular Renal failure (mild to end stage), arteries) with/without focal or difuse necrosis Proteinuria (mild to nephrotic range)
(cortical necrosis) Cortical atrophy
Renal vein thrombosis (unilateral or bilateral) Renal failure (if bilateral compromise)
Renal artery occlusion/stenosis has been reported in patients with positive assays for aPL. Some of these patients had autoimmune rheumatic conditions, mainly SLE, while others had the primary APS (PAPS).
An early observation by Ostuni et al [4] described a 13 year-old girl with SLE and severe systemic hypertension. Bilateral renal artery stenosis/thrombosis resulted in a poorly perfused kidney and cortical irregularities were present in the contralateral kidney. Hernández et al [5] reported on a young woman with sudden, severe hyper- tension and a renal infarction who, 14 years later, developed SLE. Asherson et al [6]
described a young man with PAPS, arterial hypertension, and a right renal artery stenosis with renal infarction which was thought to be caused by thrombotic occlu- sion. Ames et al [7] reported an instance of bilateral renal artery occlusion in a patient with PAPS and an unclear systemic disease. Of major interest is a paper by Rossi et al [8] reporting 2 cases of renovascular hypertension with renal artery stenosis and suggesting a pathogenetic link between renal artery stenosis, thrombo- sis, fibromuscular dysplasia, and aPL. Similar considerations were independently made by Mandreoli and coworkers [9, 10]. Particularly interesting is a report by Poux et al [11] on an athletic 35- year-old man with PAPS who suddenly developed arterial hypertension and a left renal infarction. Angiographic studies revealed com- plete thrombosis of the aorta below the renal arteries plus an extensive colateral circulation arising from the superior mesenteric artery. More recently, several cases of renal artery stenosis, mainly in young patients with PAPS, have been reported.
These consistent findings confirm that this syndrome may be a significant cause of renal artery stenosis [12–14].
In the presence of aPL, renal infarctions result from partial or total, transient or permanent occlusion of renal arteries [4, 5, 8, 9, 15, 16]. Such occlusion may be caused by diverse mechanisms such as in situ thrombosis/stenosis of a renal artery or an embolic event originating on a verrucous cardiac valve. In still other cases the cause of a renal infarction was not found [17].
Clinically, severe systemic hypertension, pain in the renal area, hematuria, and renal failure are common forms of presentation of major vessel involvement in PAPS. As commented by Hughes et al [18], arterial hypertension may be labile in early disease. Occasionally, a silent infarct is fortuitously discovered on computed tomography (CT). It cannot be overemphasized that in cases of renal artery stenosis of unknown origin, APS must be excluded. Renal scintigraphy and selective renal angiography are useful procedures to confirm diagnosis and determine the extent of damage.
Successful treatment with antihypertensive drugs [8, 15], aspirin [16], anticoagu- lant therapy [4, 7, 9, 15] as well as transluminal angioplasty [6, 12, 13] has been reported. Nephrectomy, with subsequent normalization of blood pressure and sec- ondary aldosteronism, was performed in 1 patient because the kidney was seriously and irreversibly damaged [14]. However, adverse outcomes may occur [5]. The sooner an arterial lesion causing arterial hypertension is relieved, the likelier a suc- cessful outcome.
Glomerular Capillary Thrombosis
Hyaline thrombi have been described in patients with active, usually proliferative lupus nephritis. The prevalence and significance of this finding have been carefully
studied by Kant et al [19] and Glueck et al [20]. They found an overall rate of capil- lary thrombosis of near 50% in cases of proliferative glomerulonephritis, including 78% in patients with detectable lupus anticoagulant (LA) and only 38% in those without. The presence of glomerular thrombi in the initial biopsy was a strong pre- dictor of glomerular sclerosis. Other studies have not shown an association between aPL and prognosis in lupus nephritis [21–23]. However, Moroni et al recently docu- mented the impact of aPL in 111 patients with lupus nephritis followed up for a mean of 173 ± 100 months. A strong association between aPL and the development of chronic renal insufficiency in the long term was found. With multivariate analy- sis, aPL positivity, high plasma creatinine level at presentation, and chronicity index were independent predictors of chronic renal function deterioration [24]. With these data, one should keep in mind that the detection of aPL in patients with lupus nephritis is useful not only to identify patients at risk for vascular and obstetric manifestations, but also for their potential deleterious impact on renal outcome.
Intra-renal Vascular Lesions
Thrombotic Microangiopathy
The association of the distinctive lesion known as thrombotic microangiopathy (TMA) with aPL was initially described in patients with SLE [25–27]. In another clinical setting, Kincaid-Smith and coworkers [28] showed acute or healed TMA in 22 biopsies obtained in 12 patients with LA and pregnancy-related renal failure.
Subsequently, isolated cases of TMA in patients with PAPS were reported [29, 30].
In 1992, at a time in which some still doubted about the very existence of primary
Figure 9.1. Severe and advanced glomerular thrombotic microangiopathy. Capillary lumina are occluded by severe mesangiolysis and deposition of heterogeneous subendothelial material, leading to a segmental “double contour” aspect (PAS).
PAPS, we had the opportunity to study 5 patients who had renal disease and arterial hypertension among 20 consecutive patients with PAPS [31]. Mild renal failure was present in 3 patients while 2 had end-stage renal failure requiring hemodyalisis.
Proteinuria in the mild-to-nephrotic range was also present. Biopsy findings in all 5 Figure 9.2. A small arteriole with a recent, almost occlusive, partially laminated thrombus. Some complete and fragmented white and red cells are seen (hematoxylin/eosin).
Figure 9.3. Chronic cortical lesions. There are obsolescent sclerotic glomeruli and a hypoperfused glomerulus with a wide Bowman´s space and retracted capillaries. On one of its sides there is a small arteriole with a recanalized thrombus and two lumina. On the other side there are two completely occluded arterioles showing thrombosis, recanalization, and refibrosis. A tortuous arteriole with slightly cellular subendothelial fibrosis is also seen (PAS).
patients were consistent with TMA . Some biopsies showed diffuse damage while others had only focal parenchymatous lesions. Microangiopathy involved both the vascular tree and the glomerular tufts (Fig. 9.1).
Recent and recanalized thrombi were observed (Figs. 9.2 and 9.3), as if acute lesions were superimposed on the chronic, healed damage (Table 9.2). Ultra-estruc- tural studies showed electron lucent subendothelial deposits and ischemic obsoles- cence of glomeruli in absence of histologic and immunohistochemical findings suggestive of SLE. We concluded that in PAPS, depending on the degree and exten- sion of damage, patients could have isolated hypertension, severe proteinuria, and renal failure including cortical necrosis. In chronic cases, fibrosis and focal atrophy could be found as well as arterial and arteriolar fibromuscular hyperplasia [Figs. 9.4 and 9.5).
Subsequent isolated cases or small series have confirmed our findings [32–34].
Recently, it has been emphasized that APS should be considered in the differential diagnosis of systemic hypertension and that APS-related TMA may cause isolated hypertension without significant renal impairment [35]. TMA is the characteristic histologic lesion of the microvasculature in PAPS-related nephropathy. A non- inflammatory vasculopathy with or without thrombosis (the “APS vasculopathy”) is a common finding in larger vessels. Of course, TMA is not pathognomonic of PAPS, as there is a wide range of conditions that present the same histological appearance (Table 9.3). Nochy et al [36] have confirmed our initial observations on glomerular and interlobular arteriolar lesions, and, in addition, have emphasized the common presence of focal cortical atrophy (Fig. 9.6).
Finally, other types of renal involvement, including membranous glomeru- lonephritis, IgA nephropathy, pauci-immune crescentic glomerulonephritis, glomerulonephritis with isolated C3 mesangial deposits, focal segmental glomeru-
Table 9.2. Primary antiphospholipid syndrome–associated nephropathy: main histologic features.
Acute lesions Chronic lesions
Glomerular Glomerular
Mesangial expansion Basement membrane thickening
Mesangiolysis Cellular vanishing
Glomerular capillary colapse Glomerular tuft retraction Basement membrane wrinkling Bowman’s space widening
“Double contours” with mesangial interposition Ischemic obsolescence
Translucent subendothelial deposits Segmental or global glomerular sclerosis Intracapillary thrombi
Thrombotic/hemorrhagic infarction
Arterioles Arterioles Recent occlusive thrombi Mural organized thrombi
Laminar thrombi Recanalizing occlusive thrombi
Endothelial edema/degeneration Microaneurisms Subendothelial mucoid edema Plexiform lesions
Necrosis Subendothelial fibrosis
Concentric and muscular hyperplasia Myofibroblastic proliferation Diffuse fibrosis
TMA with/without focal necrosis Ischaemic atrophy
losclerosis and, vasculitis, associated with aPL or with APS, but without SLE, have been published [37–39]. It is unclear, however, whether in addition to thrombosis, other mechanisms could also contribute to the pathogenesis of APS nephropathy.
There is evidence that aCL recognize β2-glycoprotein I (β2-GPI) on the endothelial Figure 9.4. Typical histology of an interlobular arteriole which is almost occluded by a slightly cellular mucoid material. The lumen is distorted and the muscular media is partially destroyed and fibrotic. There is interstitial fibrosis with a moderate inflammatory infiltration. A dilated tubule containing hyaline material is seen (Masson).
Figure 9.5. Chronic stage of an intraparenchymatous renal artery. Slight medial hyperplasia, fractures of the internal elastica, severe subendothelial fibrosis, myofibroblastic proliferation, and a drastic reduction of the lumen (Masson).
cell membrane, leading to increased expression of adhesion molecules and increased adhesion of monocytes on endothelial cell surface [40]. These events could perhaps explain the inflammation found in some of these uncommon cases.
Cortical Renal Ischemia
Occlusion of small isolated parenchymatous renal vessels gives rise to small foci of cortical necrosis. These are generally asymptomatic; however, if they are multiple or generalized they may lead to patchy or diffuse cortical necrosis as described in the catastrophic APS [41]. These cases feature oligo/anuria, severe hypertension, and fre- quently have a fatal outcome. Some patients eventually recover, leaving a variable degree of renal impairment expressing cortical ischemia. Isolated cases and series of patients with cortical renal ischemia and aPL have been published [17, 35, 42, 43]. One of the first reported cases [42] was a 27-year-old man with coronary occlusion, arterial hypertension, thrombophlebitis, atrial thrombus, and positive aPL. An abdominal CT
Table 9.3. Some conditions that associate with TMA.
Thrombotic thrombocytopenic purpura Haemolytic uraemic syndrome Post-partum renal failure Pre-eclampsia/eclampsia Scleroderma
Malignant arterial hypertension Oral contraceptives
Renal transplantation / allograft rejection Cyclosporine A toxicity
Chemotherapy
Figure 9.6. Focal cortical atrophy. There are ischemic glomeruli, an arteriole with “onion skin” hyperplasia of the media, and a “pin point” lumen, generalized tubular atrophy with early dilation in one, and interstitial fibrosis (Masson).
scan revealed cortex hypodensity in both kidneys. Renal biopsy showed diffuse inter- stitial fibrosis, mononuclear infiltration, sclerotic and ischemic glomeruli, and nega- tive immunofluorescence studies. These findings suggested cortical sclerosis and atrophy as sequelae from old cortical necrosis. In this patient, aside from arterial hypertension, there were no additional clinical evidences of renal damage.
Cacoub’s series of 5 cases [17] included patients with sudden presentation of malignant hypertension. While large renal vessels were patent on angiography, renal biopsy revealed glomerular ischemia, interstitial fibrosis, tubular atrophy, and vascular sclerosis with thrombosis. There was no vasculitis and immunofluores- cence studies were negative. Four of these patients did well and 1 died, probably as a result of a catastrophic syndrome.
Pérez et al [43] reported on a man with PAPS and multi-organ arterial and venous thrombosis, seemingly a catastrophic syndrome. This patient had a 2-cm renal cortical infarction and multiple petechiae in the renal cortex. At autopsy, an organizing interlobular vein thrombus plus microthrombi in the microvasculature of the medulla were found. This case illustrates medium- and small-vessel thrombo- sis affecting the intra- and extra-renal vasculature.
From the above observations, it may be concluded that cortical renal ischemia (Fig. 9.6) is a well-defined clinico-pathologic entity in patients with APS. The lesion may recover ad integrum or it may leave a variable impairment of renal function.
An additional presentation of renal cortical ischemia was described by Leaker et al [44]. This is an insidious, slowly progressive nephropathy that causes renal failure in the long term. Clinically, patients have arterial hypertension, mild proteinuria, and a slowly progressive renal failure.
In a recent multicenter study, Nochy et al [36] reported 16 patients with PAPS fol- lowed for at least 5 years, all of whom had renal biopsy. In all patients there were small vessel vaso-occlussive lesions and focal cortical atrophy was present in 10.
Renal Vein Thrombosis
The main renal vein, as well as minor veins, may thrombose in APS. Asherson [45]
first described the association between aPL and renal vein thrombosis in 2 cases of SLE with proliferative nephritis and nephrotic syndrome. An interesting study by Glueck et al [20] demonstrated renal vein thrombosis in 3 of 18 SLE patients with LA, compared with none in the 59 LA-negative patients without. Liano et al [46]
described a man with SLE, LA, and end-stage renal disease who received a renal transplant. Nineteen months after transplantation, thrombosis of the graft’s renal vein occurred and autopsy showed membranous glomerulonephritis.
Isolated cases of renal vein thrombosis have been reported in patients with PAPS [47], including 1 case with bilateral renal vein thrombosis in the postpartum period [48].
End-stage Renal Disease (ESRD)
A poorly studied issue is the occasional presence of aPL in patients with ESRD [49].
The information at hand about this interesting finding is incomplete and little more
can be said about it. Similar considerations apply to the high titers of aCL and posi- tive LA found in patients undergoing hemodialysis, a setting in which vascular access thrombosis is very common [50]. Recently, in a study of 97 hemodialysis patients, Brunet et al [51] found a prevalence of 31% of aPL (LA in 16.5% and aCL in 15.5%). The presence of aPL was independent of age, time on dialysis, gender, type of dialytic membrane used, drugs used, or presence of hepatitis B or C. There was a higher prevalence of aPL when the cause of the ESRD could not be deter- mined. Analyzing the association between vascular access thrombosis and aPL, they found a striking correlation with the presence of LA (62% vs. 26%; P = 0.01) but not with aCL.
Renal Transplantation
Very few studies have addressed the impact of aPL on renal transplantation.
Reports of aPL-related morbidity among SLE transplant patients are limited by the relatively small number of subjects available for study at any given center.
In the UCSF study, 15.4% of allograft failures were attributed to aPL-associated events [52].
Radhakrishna et al [53] in a retrospective study of SLE, compared 8 patients with aCL to 5 patients without, transplanted during the same period. Thrombotic episodes occurred in 3 patients in the aCL-positive group but none in the aCL-nega- tive group. Neither of the 2 groups differ in the number of rejection episodes, rate of graft loss, or renal function at follow up. The authors concluded that patients with SLE and aCL can be successfully transplanted.
Findings have been quite different in PAPS. Mondragón-Ramírez et al [54]
reported 2 cases of PAPS with renal TMA who underwent renal transplantation and in whom, despite intensive anticoagulant therapy, the disease relapsed in the graft.
Massive thrombosis in the graft in 1 case [Figs. 9.7 and 9.8) and TMA in the other suggested recurrence of the disease. We postulated that the surgical procedure plus endothelial damage, a common feature of allograft rejection, may act synergistically in amplifying the hypercoagulable state. Both patients also had thrombosis in the vascular access used for hemodialysis as has been reported by others [49, 50].
In an interesting report by Knight et al [55], a woman with aCL lost a renal allo- graft in the immediate postoperative period due to renal artery thrombosis. Six months later she underwent successful re-transplantation under full anticoagula- tion despite the presence of postoperative bleeding.
Vaidya et al [56] confirmed that patients with APS are at high risk for post-trans- plant renal thrombosis. Within a group of 78 patients who received renal transplant, 6 had APS. Each of these 6 patients thrombosed their renal allografts within a week of the transplant. In contrast, the remaining 72 patients were all doing well 1 year post-transplant. More recently, isolated cases as well as retrospective and prospec- tive studies have addressed the impact of aPL on renal transplantation. In 1999, a retrospective study in 96 patients with ESRD quantified the negative impact of aPL on renal transplantation [57]. In another multicenter study, 502 ESRD patients awaiting renal transplantation were screened for APS. The potential risks associ- ated with APS were assessed, and strategies for therapeutic intervention were reviewed. The conclusion of this study was that patients with APS are at high risk of
post-transplant renal thrombosis and that anticoagulant therapy could prevent this complication [58]. Interestingly, the same group of investigators reported their experience with 9 APS renal-transplant patients. Seven patients were treated with coumadin, whereas 2 were treated with heparin. Of the 2 patients treated with Figure 9.7. Fragment of the transplanted kidney in a female patient with PAPS. The whole vascular tree (from the intraparenchymatous vessels to the main intrarenal artery and vein) shows recent thrombotic occlusion (hematoxilin/eosin).
Figure 9.8. This micrograph belongs to the same kidney shown in Figure 7. There is generalized thrombosis of the microvasculature including glomerular capillaries, afferent arterioles, and interlobular arteries. Generalized necrosis without inflammatory cell infiltration is also observed (Masson).
heparin, 1 had early allograft loss, whereas the other patient is doing well at 5 years post-transplant. Of the 7 patients treated with coumadin, 2 are doing well, 2 had early allograft loss, and the remaining 3 patients returned to dialysis after they were taken off the coumadin because of bleeding complications. The conclusions of this study are that anticoagulation therapy is beneficial to some but not all APS renal- transplant patients and, in addition, bleeding complications are a serious side effect in this setting [59]. With these data, one should question which patients with APS should be transplanted and which therapeutic intervention(s) could be used to avoid a catastrophic outcome.
Concluding Comments
In agreement with Nochy et al [36], we believe the TMA to be the characteristic nephropathy of PAPS. The lesion may have an abrupt or an insidious onset and may vary in severity and exent. All vascular structures of the kidney may be affected including glomeruli, arterioles, and parenchymatous arteries. Acute lesions as they heal give way to reparative fibrosis and focal atrophy. They are worsened by recur- rent acute damage. In other cases, the lesion is insidious and slowly progressive, causing similar focal reparative fibrosis and tissue atrophy, arterial hypertension, and in some instances ESRD.
In patients with PAPS, renal involvement is probably underestimated. Hopefully, current knowledge of renal disease in APS will soon permeate all branches of inter- nal medicine making possible an appropriate diagnosis.
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