Version May 2024
INTRODUCTION — The antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by persistent autoantibodies directed against either phospholipids or plasma proteins bound to anionic phospholipids [1,2]. The pathogenesis of the syndrome is complex, involving a multiplicity of factors [2]. Patients with the APS may display a constellation of clinical features including venous, arterial, and microvascular thromboses, which can be associated with valvular heart disease, thrombocytopenia, livedo reticularis, neurologic findings, and recurrent fetal losses [1].
Antiphospholipid-related kidney disease, and so-called antiphospholipid nephropathy, may be found with any of these other clinical features. This disorder is referred to as the primary APS when it occurs alone without another associated autoimmune disease. Among patients with systemic lupus erythematosus (SLE), 20 to 30 percent will have clinically relevant elevated levels of antiphospholipid antibody titers [3]. Elevated antibody titers can also be found in other rheumatic diseases, with certain infections, in patients taking specific medications, and among patients with pregnancy complications, venous thromboses, or stroke [4].
Types of antiphospholipid antibodies (aPL) that have been characterized include:
●Antibodies causing a false-positive Venereal Disease Research Laboratory (VDRL) test
●Lupus anticoagulants
●Anticardiolipin antibodies (aCL)
●Antibodies to beta2-glycoprotein I
There appears to be a relationship between the isotype and titer of aPL and the risk of thrombotic events. Higher titers of immunoglobulin G (IgG) aPL, for example, are associated with a greater incidence of thrombotic events [5].
The kidney is one of the organs that may be involved in APS. Kidney complications may directly result from thrombotic events associated with these antibodies, including microvascular glomerular disease, large vessel arterial and venous renal thromboses, chronic vasoocclusive disease, and coagulation problems relating to dialysis or kidney transplantation [5-12].
The pathology, manifestations, and treatment of kidney involvement in patients with APS are presented here. General discussions of the clinical manifestations, diagnosis, and treatment of this disorder are presented elsewhere:
●(See "Clinical manifestations of antiphospholipid syndrome".)
●(See "Diagnosis of antiphospholipid syndrome".)
●(See "Management of antiphospholipid syndrome".)
●(See "Catastrophic antiphospholipid syndrome (CAPS)".)
KIDNEY MANIFESTATIONS OF ANTIPHOSPHOLIPID SYNDROME — The prevalence of kidney involvement in patients with primary antiphospholipid syndrome (APS) has been reported in up to 25 percent, although the frequency is far lower in most series [5,7-9,12,13]. In one cohort of 160 patients with primary APS from Northern Italy, signs of kidney involvement were present in 9 percent of patients [14]. Antiphospholipid antibodies (aPL) frequently occur in patients with lupus, in whom kidney disease is more frequently caused by immune deposits. (See "Lupus nephritis: Diagnosis and classification".)
Kidney disease in primary APS — Kidney involvement in primary APS is generally characterized pathologically by noninflammatory occlusion of a broad spectrum of renal blood vessels, ranging from glomerular capillaries to the main renal artery and vein (picture 1A-D) [8,12,15-18].
aPL-associated nephropathy — When small renal vessels, such as glomerular capillaries, are involved, the pathological findings resemble those found in other diseases associated with a thrombotic microangiopathy (TMA), including the hemolytic-uremic syndrome, and thrombotic thrombocytopenic purpura. When seen in patients with aPL, they have been called "aPL-associated nephropathy" [5,7,8,13,19] (see "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)"):
●Involved arteries and arterioles often have a thrombotic lesion, resulting in reactive intimal mucoid thickening, subendothelial fibrosis, and medial hyperplasia [8].
●Affected glomerular capillaries reveal thrombi with associated mesangiolysis, mesangial interposition along the glomerular capillary wall, and electron lucent areas in the subendothelial space.
●Focal atrophy of the cortex in association with interstitial fibrosis may be observed, presumably resulting from tissue ischemia.
If kidney biopsy is performed later in the course of the disease, focal segmental glomerulosclerosis may be a prominent finding as a sequel of the glomerular TMA [20].
The clinical features associated with the thrombi in the glomeruli and small arteries are variable [21]. Some patients have only asymptomatic, mild proteinuria (<2 g/day) with normal kidney function, while others develop acute or subacute kidney injury with proteinuria (which can reach the nephrotic range), an active urine sediment (that can include red cell casts), and often marked hypertension [8,15,22].
Large vessel disease — Large renal arterial thrombosis with renal infarction can present with unilateral or bilateral flank pain, hematuria, and decreased kidney function [5,7,8,13]. Renal angiography, or computed tomography or magnetic resonance angiography (MRA) should be performed to confirm the diagnosis. APS can be also associated with arterial disease and hypertension without evidence of thrombosis of the renal arteries [23,24]. In one study of 260 patients, for example, 26 percent of those with uncontrolled hypertension and APS were found to have renal artery stenosis by MRA [23].
Renal vein thrombosis, when it occurs, may be silent or, if acute and complete, may present with sudden flank pain and a decrease in kidney function [11,25].
Other glomerular lesions associated with primary APS — Other glomerular lesions that have been described in patients with primary APS including membranous nephropathy, minimal change disease, and pauci-immune glomerulonephritis [14,26]. In a retrospective study of 160 patients who were diagnosed with primary APS, kidney involvement (defined as serum creatinine >1.4 mg/dL [124 micromol/L] and/or proteinuria >0.3 g/day with or without hematuria) was identified in 14 [14]. Ten of the 14 patients had a kidney biopsy that showed membranous nephropathy (n = 4), diffuse proliferative glomerulonephritis (n = 2), TMA (n = 2), and vascular lesions consistent with chronic antiphospholipid nephropathy (n = 2). Both patients who had diffuse proliferative glomerulonephritis developed full-blown lupus 13 and 18 years after the diagnosis of primary APS. At a mean follow-up of 8.5 years (range 6.9 to 14 years), none of the patients with membranous nephropathy had developed clinical evidence of lupus, although it is possible that lupus-related signs or symptoms were suppressed by immunosuppressive therapy.
Kidney disease in APS associated with systemic lupus erythematosus — Patients with lupus and aPL commonly have a history of systemic thromboses, fetal loss, neurologic disorders, and thrombocytopenia [5,27,28]. In patients with lupus, the principal laboratory features that correlate with the presence of high titers of immunoglobulin G (IgG) aPL are thrombocytopenia, the presence of a false-positive Venereal Disease Research Laboratory (VDRL) test for syphilis (fluorescent treponemal antibody [FTA] negative), and a prolonged activated partial thromboplastin time (aPTT) [5,12,29]. Kidney disease in this setting may result from microthrombi and/or deposits of immune complexes.
Isolated microangiopathic thrombosis is a relatively unusual finding in patients with APS and lupus. Only approximately 10 percent of such patients in whom kidney biopsies are performed show glomerular microthromboses as the major histopathologic finding. Nevertheless, aPL can cause significant kidney damage in patients with lupus [19,30]. These histologic and clinical features are similar to those with the APS alone or those with lupus-like features in whom the American Rheumatism Association (ARA) criteria for a diagnosis of systemic lupus erythematosus (SLE) are not fulfilled [19,30].
To better address the relationships among thrombi, aPL, kidney dysfunction, and traditional lupus nephritis, a retrospective study evaluated the findings on kidney biopsy in 114 patients with SLE and kidney dysfunction [31]. The following results were noted:
●Vaso-occlusive lesions were found in approximately one-third of biopsies in addition to, or independent of, traditional immune complex lupus nephritis.
●Thrombi independently contributed to elevations in the serum creatinine concentration and the development of hypertension.
●The presence of renal thrombi correlated with the presence of a lupus anticoagulant, but not with anticardiolipin antibodies (aCL).
APS in patients with SLE can occur in addition to and independent of lupus nephritis [31,32]. In a review of 111 patients with lupus nephritis who were followed for a mean of almost 15 years and were tested regularly for aCL and lupus anticoagulant, the overall prevalence of aPL was 26 percent. aPL occurred more frequently in patients with membranous lupus (50 versus 22 percent with other lesions).
It is important to document the presence of glomerular microthromboses in patients with the APS and SLE since the therapy for TMA differs from the immunosuppression required for immune complex-mediated lupus nephritis. Such thrombi often recanalize in the absence of an inflammatory infiltrate and in the absence of immune deposits on immunofluorescence or electron microscopy.
The relationship between aPL and the overall risk of progressive chronic kidney disease (CKD) is not entirely clear [32-34]. A prospective, long-term study (median follow-up of 167 months) evaluated 111 patients with lupus nephritis, of whom 29 had aPL [32]. There was a significant correlation between antibody presence and the eventual development of CKD (relative risk [RR] 2.2). Although not all studies have confirmed such an association between the presence of aPL and a progressive kidney course [34], most studies confirm that the presence of thrombotic nephropathy in patients with lupus nephritis is an independent risk factor for a poor kidney outcome [35,36].
The presence of aPL may also be associated with a higher mortality in patients with lupus nephritis [37].
ANTIPHOSPHOLIPID SYNDROME IN END-STAGE KIDNEY DISEASE — Antiphospholipid antibodies (aPL) can occur in patients with end-stage kidney disease treated with maintenance hemodialysis or kidney transplantation. (See "Hemodialysis arteriovenous graft dysfunction and failure".)
Hemodialysis — Several studies have found that patients on maintenance hemodialysis have a high prevalence of aPL, a finding associated with an increased incidence of thrombotic events [38-41]. In one study, for example, aPL were present in 31 percent of 97 hemodialysis patients (the lupus anticoagulant and anticardiolipin antibodies [aCL] in 17 and 16 percent, respectively) [38]. The frequency of vascular access thrombosis was much higher in the patients with aPL, as measured by the lupus anticoagulant (62 versus 26 percent in those without these antibodies). Similar findings were noted in another report in which a significant increase in the odds of having two or more episodes of arteriovenous (AV) graft thrombosis was found among the patients with raised aPL titers [39].
The incidence of aPL may vary with the type of hemodialysis access used. This was suggested in a cross-sectional study that evaluated hemodialysis patients at a single dialysis facility: 22 percent of 74 patients with AV grafts had a raised titer of immunoglobulin G (IgG) aPL versus only 1 of 17 patients (6 percent) with AV fistulas [39]. Whether AV grafts induce aPL or patients with aPL require AV grafts could not be determined.
The experience at one major medical center lends further support to these findings. In a review of 230 patients undergoing chronic hemodialysis, the following results were noted:
●Titers of IgG aPL were elevated in 26 percent
●Titers of immunoglobulin M (IgM) aPL were elevated in 4 percent
●Titers of both antibodies were elevated in 3 percent
The mean time to AV graft failure was significantly decreased in the group with elevated IgG antibodies, even though there was no difference in AV fistula clotting between those with and without high IgG antibody titers.
There does not appear to be an association between the development of aPL and age, sex, or dialysis duration [38]. However, the incidence of such antibodies appears to correlate positively with the type of dialysis modality as well as the use of dialysis since a much lower incidence of aPL has been found both in patients with kidney function impairment in whom dialytic support is not yet required and in those treated with peritoneal dialysis [40,42,43].
Kidney transplantation — There is increasing evidence that patients with a positive aPL or the antiphospholipid syndrome (APS) have a worse outcome after kidney transplantation [5,44,45]. In one series of over 1300 kidney recipients, lupus anticoagulant-positive patients had a high rate of vascular damage in their allograft and poor one-year outcomes [44]. A substantial number of kidney transplant recipients have circulating aPL, which can damage the allograft [46-48]:
●In a retrospective study of 178 transplant recipients, 28 percent had aPL [47]. Compared with patients without such antibodies, these individuals had a significantly higher incidence of arterial (18 versus 6 percent, p<0.001) and venous (8 versus 2 percent, p<0.001) thrombosis; testing of pretransplant sera revealed that the aPL were present prior to the operation in 85 percent of patients.
●A second retrospective series, which evaluated transplant recipients with systemic lupus erythematosus (SLE), also found a high incidence of significant thrombotic events among those with aPL (60 versus 8 percent in patients without these antibodies) [49].
Although suggestive, these retrospective observations cannot prove causality. Another retrospective study, for example, reported no increased incidence in allograft loss or reduction in glomerular filtration rate among the 61 of 337 patients with positive aCL. In this study, there was increased use of warfarin in those with positive antibodies (20 versus 7 percent) [50]. However, early allograft loss was observed in two of five patients with very high aCL titers who were not being anticoagulated.
In addition to systemic thrombotic events, a renal thrombotic microangiopathy (TMA) may be observed in hepatitis C virus (HCV)-infected kidney transplant recipients with aCL. This association was suggested in a report of 18 anti-HCV-positive patients, five of whom developed renal TMA between 5 and 120 days after transplantation [51]. aPL were found in all five of these patients but in only 1 of the 13 without a microangiopathy. The hypothesis that aCL, HCV infection, and renal thrombosis were correlated was supported by the observation that normal aCL titers were found in the seven HCV-negative transplant recipients who presented with renal TMA/hemolytic-uremic syndrome during the same time period and served as a control group.
TREATMENT — The treatment of patients with antiphospholipid syndrome APS who have kidney disease is generally similar to that of patients without kidney disease [5,7,8,13,52]. Patients with evidence of venous or arterial thromboembolic disease, thrombotic microangiopathy (TMA) in the glomeruli and small arteries, or thrombi in the larger vessels must be treated to avoid life-threatening vascular damage. In general, patients with APS-associated kidney disease should be anticoagulated with vitamin K antagonists [53]. Although not applicable to all patients with APS, data suggest that anti-factor Xa therapy with either apixaban or rivaroxaban is inferior to vitamin K antagonist therapy [54-56]. (See "Management of antiphospholipid syndrome".)
Treatment of catastrophic APS (CAPS) is presented separately. (See "Catastrophic antiphospholipid syndrome (CAPS)", section on 'Management'.)
Issues related to the general therapy of thromboembolic events in patients with the APS are discussed in detail elsewhere. Summarized briefly, moderate-intensity warfarin (target international normalized ratio [INR] of 2 to 3) appears to be as effective as more intensive anticoagulation [57,58]. (See "Management of antiphospholipid syndrome", section on 'Secondary thrombosis prevention'.)
The use of antithrombotic therapy for primary prevention in APS is controversial. Because many patients with antiphospholipid antibodies (aPL) do not experience thrombotic events or have evidence of renal thrombosis, indiscriminate anticoagulation of such patients places a large population at risk for bleeding to achieve a dubious benefit. However, some experts recommend low dose aspirin for asymptomatic carriers of aPL [53]. It is reasonable to administer prophylactic anticoagulation to some patients with aPL who have other conditions associated with high thrombotic risk. For example, patients with APS who have membranous nephropathy may warrant prophylactic anticoagulation, even if nephrotic syndrome and low serum albumin concentrations are absent. (See "Hypercoagulability in nephrotic syndrome", section on 'Prevention of thromboembolism'.)
Immunosuppressive therapy generally has little effect on the titers of aPL. Most immunosuppressive agents have been used in isolated cases or small numbers with varied success [59]. However, eculizumab, a humanized monoclonal antibody against the fifth component of complement, has been successful in rare anecdotal cases to treat recurrent thromboses after kidney transplantation [60,61].
Hemodialysis — Patients with APS treated with hemodialysis have an increased incidence of recurrent thrombosis in arteriovenous (AV) grafts [38-41]. In such patients, treatment with warfarin may increase AV graft survival [6]. However, given the risks of bleeding in anticoagulated patients, many would only anticoagulate patients who have repeat AV graft clotting.
Kidney transplantation — Patients with a positive aPL or the APS have a worse outcome after kidney transplantation than those without these findings [5]. Patients with systemic lupus erythematosus (SLE), a positive aPL, a history of thromboembolic events and lupus nephritis, as well as those with the APS, may benefit from continued warfarin therapy after kidney transplantation [62-64]. If untreated, these patients appear to be at risk for both intrarenal and systemic clotting events [46,50,62]. Based on the incomplete data, many transplant nephrologists anticoagulate all patients with aPL and a history of coagulation events during the peritransplant period. It is unknown how long such treatment should be continued or whether it should be continued indefinitely. As examples:
●One study reported the outcomes of 11 kidney transplant recipients with the APS, of whom four were treated with anticoagulant therapy after transplantation [62]. All seven patients not administered anticoagulants lost their allograft to renal thrombosis within one week of surgery; by comparison, three of four treated patients had functioning allografts for over two years, but the remaining patient also thrombosed his graft within one week of the procedure. No allografts were lost to renal thrombosis among 37 other patients with high titers of anticardiolipin antibodies (aCL) but no previous history of thrombosis.
●A protective effective of anticoagulation was also suggested in another report in which five patients at high risk for thrombosis were treated preemptively with postoperative heparin and subsequently with warfarin [65]. Allograft thrombosis occurred in one patient who received enoxaparin rather than warfarin. The target INR for warfarin therapy was 2.0 to 2.5.
●Inhibitors of the mammalian target of rapamycin (mTOR) may decrease the recurrence of APS-associated vascular lesions among kidney transplant recipients [66]. The activation of mTOR signalling pathways was demonstrated in cultured vascular endothelial cells treated with immunoglobulin G (IgG) antibodies from patients with APS. Allograft biopsies from 10 transplant recipients with aPL who were receiving the mTOR inhibitor, sirolimus, showed decreased hyperplasia of endothelial cells compared with biopsies from 27 patients with aPL who did not receive sirolimus. Additionally, allograft function appeared to be better preserved among APS patients who received sirolimus. This observational study offers insights into the pathogenesis of APS but requires independent confirmation before recommendations regarding treatment can be made [67].
Acute kidney injury — Selected patients with acute kidney injury (AKI) may respond either to plasmapheresis, which presumably acts by removing the pathogenic antibody [8,9,68], or to corticosteroids and chronic anticoagulation [69]. In an uncontrolled report of 12 patients, for example, complete kidney function recovery occurred only in the two patients treated with plasma exchange [8].
The optimal apheresis regimen for AKI is uncertain. However, a prescription of three to five one-plasma volume exchanges over a seven-day period should produce substantial lowering of aPL levels. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute kidney injury in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Antiphospholipid syndrome (Beyond the Basics)" and "Patient education: Systemic lupus erythematosus (Beyond the Basics)" and "Patient education: Hemodialysis (Beyond the Basics)" and "Patient education: Dialysis or kidney transplantation — which is right for me? (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Overview – The antiphospholipid syndrome (APS) is characterized by antibodies directed against phospholipids or plasma proteins bound to phospholipids. APS may occur alone (primary APS) or in association with systemic lupus erythematosus (SLE), other rheumatic diseases, and certain infections and medications. (See 'Introduction' above.)
●Kidney disease in primary APS – Primary APS causes noninflammatory occlusion of renal blood vessels that, depending on the type of the involved blood vessels, results in renal infarction, ischemic changes, or in thrombotic microangiopathy (TMA) involving the glomeruli. (See 'Kidney disease in primary APS' above.)
•Antiphospholipid-associated nephropathy – Among patients with glomerular involvement, histology often resembles the hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura. In this setting, the lesion has been called antiphospholipid-associated nephropathy. (See 'aPL-associated nephropathy' above.)
•Large vessel disease – Patients who have large vessel involvement present with unilateral or bilateral flank pain, hematuria, and decreased kidney function. (See 'Large vessel disease' above.)
•Other glomerular lesions – Other glomerular lesions that may be observed include membranous nephropathy, minimal change disease, and pauci-immune glomerulonephritis. (See 'Other glomerular lesions associated with primary APS' above.)
●APS associated with SLE – Patients with APS associated with SLE present with systemic thromboses, fetal loss, neurologic disorders, thrombocytopenia, a false-positive Venereal Disease Research Laboratory (VDRL) test for syphilis, and a prolonged activated partial thromboplastin time (aPTT). Among such patients, kidney disease may result from microthrombi and/or deposits of immune complexes. (See 'Kidney disease in APS associated with systemic lupus erythematosus' above.)
●APS in end-stage kidney disease
•Patients on maintenance hemodialysis have a high prevalence of antiphospholipid antibodies (aPL) that are associated with an increased incidence of thrombotic events, often involving the vascular access. The incidence of such antibodies appears to correlate with the use of dialysis and with the type of dialysis but not with age, sex, or dialysis duration. (See 'Hemodialysis' above.)
•A substantial number of kidney transplant recipients have circulating aPL, which can damage the allograft. A renal TMA has also been observed in hepatitis C virus (HCV)-infected kidney transplant recipients with aPL. (See 'Kidney transplantation' above.)
●Management – The treatment of patients with APS who have kidney disease is generally similar to that of patients without kidney disease. Patients with TMA in the glomeruli and small arteries or thrombi in the larger vessels must be treated with anticoagulation to avoid life-threatening vascular damage. (See "Management of antiphospholipid syndrome".)
●Catastrophic APS (CAPS) – Treatment of CAPS is presented separately. (See "Catastrophic antiphospholipid syndrome (CAPS)", section on 'Management'.)
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