Role of antiphospholipid antibodies in kidney disease: Risk factors, immunopathogenesis, and diagnosis

Abstract

Antiphospholipid antibodies (aPLs) are a heterogeneous group of autoantibodies that include anticardiolipin antibodies, anti-β2 glycoprotein I antibodies, and lupus anticoagulant. The presence of aPLs is the main characteristic feature of antiphospholipid syndrome (APS), an autoimmune disease with multifactorial etiology. Kidney involvement is a well-recognized complication associated with both primary and secondary APS. Kidney involvement in APS presents with renal artery thrombosis, renal vein thrombosis, allograft loss due to thrombosis after kidney transplantation, and injury to the renal microvasculature, also known as APS nephropathy (APSN). APSN is the characteristic manifestation of kidney involvement in APS and occurs as a result of vaso-occlusive disease in the intrarenal vasculature. Diagnosis and risk stratification of APS are complex and still evolving. This review synthesizes and updates the available evidence in literature regarding risk factors, pathogenesis, and diagnosis of APS and APSN.

Key Words: Antiphospholipid syndrome; Antiphospholipid nephropathy; Antiphospholipid antibodies; Thrombosis; Allograft; Kidney infarction

Core Tip: Antiphospholipid syndrome (APS) is an autoimmune disorder defined by the presence of antiphospholipid antibodies such as anticardiolipin, anti-β2 glycoprotein I, and lupus anticoagulant. Renal involvement is a significant yet underrecognized complication of both primary and secondary APS. Manifestations include renal artery and vein thrombosis, APS nephropathy (APSN), and renal allograft thrombosis. APSN, a hallmark of renal APS, results from vaso-occlusive injury to the intrarenal microvasculature. Accurate diagnosis and risk assessment remain challenging due to evolving criteria and heterogeneous presentation. This review consolidates current evidence on APS and APSN, emphasizing risk factors, underlying mechanisms, and diagnostic approaches.

INTRODUCTION

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by the presence of circulating antiphospholipid antibodies (aPLs), thrombotic episodes in the arterial or venous circulation, and pregnancy-related complications[1]. aPLs, a hallmark of APS, comprise a heterogeneous group of autoantibodies, namely lupus anticoagulant (LA), anticardiolipin antibodies (aCLs), and anti-β2 glycoprotein I (anti-β2GPI) antibodies directed against phospholipid and phospholipid-binding proteins at cell surfaces[2-4].

APS may be classified as either primary or secondary, with the secondary form typically associated with other underlying autoimmune diseases, most commonly systemic lupus erythematosus (SLE)[5]. APS diagnosis requires both clinical (thrombosis and/or obstetric complications) and laboratory evidence (confirmed presence of aPLs). This is stated in the Sapporo, Japan international consensus (Sapporo criteria), in the 2006 revised Sydney criteria, and more recently in the revised 2023 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) APS classification criteria[6,7]. APS can affect people of any sex and can be diagnosed at any age. In general, it seems to affect women more often than men, and is often diagnosed between the ages of 20 and 40 years[8]. The presence of aPLs is not the only risk factor necessary for developing APS; the coexistence of other factors can act as triggers like smoking, hypertension, obesity, taking estrogen, extended periods of inactivity such as bed rest, and having an associated autoimmune disease like lupus[9]. APS may involve any organ in the body due to vascular thrombosis. Kidneys are frequently affected in both primary and secondary forms of APS. Renal involvement occurs in 2.7% of patients with APS and may manifest as renal artery stenosis, renal vein thrombosis, thrombotic microangiopathy (TMA), and chronic vascular nephropathy[8,10-12]. Renal manifestations associated with APS are summarized in Table 1.

Table 1 Renal complications of antiphospholipid syndrome.

Hypertension

Renal artery stenosis or thrombosis (unilateral or bilateral)

Renal vein thrombosis (unilateral or bilateral)

Ischemic nephropathy

APS nephropathy

Acute: Thrombotic microangiopathy

Chronic vaso-occlusive lesions: Cortical ischemia or infarction, interstitial fibrosis, tubular atrophy, specific intrarenal vasculopathy, arteriosclerosis, intimal hyperplasia, tubular thyroidization

Vascular access thrombosis in patients udergoing hemodialysis

Renal allograft

De novo or relapse of APSN of the allograft

Renal vein thrombosis

Renal artery thrombosis/stenosis

APS: Antiphospholipid syndrome; APSN: Antiphospholipid syndrome nephropathy.

In this review, we outline the role of aPLs in kidney disease, risk factors, and the immunopathogenesis of APS nephropathy (APSN).

EPIDEMIOLOGY

The prevalence of aPL positivity in the general population is about 1%-5.6%. The overall prevalence of APS ranges from 20 to 50 cases per 100000 people. Approximately 30%-40% of patients with SLE have aPL, and about one-third of these individuals develop thrombosis during their follow-up period[13]. According to the European definition of rare diseases, the prevalence of APS is 5 cases/10000 individuals[14-18]. aPLs can be found in the general population without having overt APS. Transient and low-titer aPL positivity with no clinical implications has been reported in association with several conditions such as infections, malignancies, and some medications[19-21]. APS has been identified in about 13.5% of stroke cases, 11% of myocardial infarction cases, 9.5% of patients with deep vein thrombosis, and 6% of those presenting with obstetric complications[15].

Although APS can affect any organ system, renal involvement has emerged as a significant contributor to morbidity. The prevalence of APSN is not fully established due to variability in diagnostic criteria and underreporting, particularly in patients with non-lupus APS. However, renal manifestations are increasingly recognized in both primary APS (PAPS) and secondary APS, particularly in association with SLE. APSN is most commonly identified during histopathologic evaluation, especially in patients undergoing renal transplantation or biopsy due to hypertension, proteinuria, or progressive renal dysfunction. Studies estimate that 20%-40% of patients with APS may develop renal involvement, with APSN being one of the common histopathological findings[11,22].

In patients with lupus with APS, the prevalence of APSN is reportedly as high as 25%-30%, particularly in those undergoing renal biopsy for unexplained renal dysfunction[12,23].

The prevalence of APSN in patients with SLE in Western population is 23%-32% in patients who underwent renal biopsies[24].

Tektonidou et al[12] reported the prevalence of APSN in 39.5% of patients with SLE with aPL, compared with only 4.3% of the 70 patients with SLE without aPL, suggesting an important role of aPL in the pathogenesis of APSN.

Patients with APSN develop hypertension and have increased serum creatinine levels and progression of histologic lesions, all of which are associated with a poor renal outcome.

aPLs

Routinely tested aPLs are aCLs (immunoglobulin G [IgG]/IgM isotypes) and anti-β2GPI (IgG/IgM isotypes), detected by the enzyme-linked immunosorbent assay. In addition, these also include LA, which can be identified through coagulation tests such as prothrombin time or the Russell viper venom test. The presence of LA is regarded as a significant risk factor for thromboembolic events and pregnancy-related complications[25]. Patients who are triple-positive for all three standard assays are at higher risk for developing thrombotic and obstetric complications. A retrospective Italian study involving more than 600 patients found that triple positivity for aPL (LA+, aCL+, and anti-β2GPI+) was associated with a significantly higher risk of thromboembolic events (odds ratio [OR]: 33.3) compared to isolated positivity for either anti-β2GPI IgG/IgM or aCL IgG/IgM[26].

aPLs of the IgG and IgM isotypes against β2GPI and aCLs are well-established laboratory criteria for the diagnosis of APS. However, recent studies have highlighted the potential diagnostic relevance of IgA isotype, particularly in patients who exhibit clinical features of APS but test negative for the conventional IgG/IgM isotypes, commonly referred to as seronegative APS. IgA aPLs, especially IgA anti-β2GPI, have been associated with thrombotic events and obstetric complications, suggesting a pathogenic role in APS[27,28].

Furthermore, the inclusion of IgA isotype testing may increase the diagnostic sensitivity in patients with SLE or other autoimmune diseases, where isolated IgA positivity can sometimes be the sole immunological marker[29].

IgA aCL and anti-β2GPI can also be detected in APS. Testing for these antibodies when other aPL tests are negative and APS is suspected is recommended. IgA anti-β2GI antibodies directed against domain IV/V of β2GPI represent an important subgroup of clinically relevant aPLs[30]. IgA anti-β2GI is detected in approximately 30% of patients undergoing chronic hemodialysis and is associated with thrombotic events[31,32]. The presence of pre-transplant IgA anti-β2GPI has been identified as a risk factor for allograft thrombosis and delayed graft function[33].

Nevertheless, current classification criteria, including the 2006 Sydney and 2023 ACR/EULAR criteria, do not formally recognize IgA aPLs due to variability in assay standardization and lack of conclusive evidence from large prospective studies. Despite this, several experts advocate for the inclusion of IgA aPLs in clinical assessment, particularly in patients with high clinical suspicion but negative standard tests, reinforcing their potential utility in improving APS diagnosis[34].

Seronegative APS is increasingly recognized as a distinct subtype characterized by the absence of detectable “classic” aPLs and the presence of “non-criteria” clinical features. This form is often linked to the presence of non-conventional aPLs. These antibodies include antiphosphatidylethanolamine, aPLs to negatively charged phospholipids other than cardiolipin (antiphosphatidylserine, antiphosphatidylinositide, and antiphosphatidic acid), antiprothrombin, and antiphosphatidylserine/prothrombin. These non-classic antibodies have been linked to an increased risk of thrombotic events and obstetric complications. However, only about 6% of patients with seronegative APS actually develop thrombotic events[35,36].

RENAL INVOLVEMENT IN APS

Renal involvement in APS is increasingly recognized as a significant manifestation, particularly in patients with PAPS or those with associated secondary APS. The most common renal manifestations include renal artery thrombosis, renal vein thrombosis, TMA, and chronic renal ischemia leading to hypertension and progressive renal insufficiency. APSN, a distinct histopathological entity, encompasses a spectrum of vascular lesions including fibrous intimal hyperplasia, focal cortical atrophy, arterial and arteriolar thrombosis, and TMA, often in the absence of glomerular immune complex deposition[11]. All components of the kidney parenchyma are involved at some stage of APSN, as shown in Figure 1.

Figure 1  Main targets of antiphospholipid antibody-induced injury in antiphospholipid syndrome nephropathy.

Early recognition of renal manifestations is essential, as they may be clinically silent or present with only mild proteinuria and hypertension. Kidney biopsy remains crucial for diagnosis in uncertain cases, particularly when considering differential diagnoses such as LN in patients with SLE. Management involves long-term anticoagulation, usually with warfarin, targeting an international normalized ratio (INR) of 2-3; however, patients with recurrent thrombosis or catastrophic APS (CAPS) may require more intensive treatment strategies[37].

Hypertension

Hypertension is a frequent clinical feature of APS, occurring not only in cases of renal infarction but also as a result of renal artery stenosis or APSN. The underlying cause of hypertension in APS is typically related to stenosis or occlusion of the renal arteries or intrarenal vascular lesions. Hypertension is a common feature of the PAPS and secondary APS. Nochy et al[22] reported that in patients with PAPS, hypertension was observed in 93% of cases and was sometimes the sole clinical indicator of nephropathy. Similarly, in a series of secondary APS cases described by Kleinknecht et al[38], all patients with SLE and APS exhibited severe hypertension accompanied by renal insufficiency. Subsequent studies have indicated that hypertension serves as a marker of nephropathy in both PAPS and secondary APS[37,39]. Hypertension in APS is often severe, and some patients may present with hypertensive emergencies. In rare cases, it may be accompanied by microangiopathic hemolytic anemia. It is important to note that both microangiopathy and occlusion of the main renal artery can contribute to the development of malignant hypertension in APS. Cacoub et al[40] studied the kidney lesions in a group of 5 patients with APS complicated by hypertensive crises in the absence of LN. These lesions were represented by ischemic glomeruli without proliferation, focal intimal fibrosis, and thrombosis. In patients with PAPS or secondary APS who develop sudden-onset hypertension, evaluation of both the renal arteries and the intrarenal microvasculature is recommended[11].

Renal artery thrombosis and infarction of the kidney

Renal artery stenosis or occlusion has been documented in several case reports and series involving patients who are aPL-positive with SLE as well as those with PAPS. The first case of renal artery involvement in APS was reported by Ostuni et al[41]. They described hypertension and renal artery thrombosis in a 13-year-old girl in association with high titers of aCLs and a false-positive venereal disease research laboratory test. Asherson et al[42] reported a case of a young man with PAPS who suddenly developed severe hypertension due to right renal artery stenosis. Ames et al[43] reported patients who presented with hypertension and oliguria, bilateral renal artery occlusion on renal arteriography, and a high titer of circulating aPLs. Sangle et al[44], using magnetic resonance angiography (MRA), found that 20 of 77 (28%) patients with APS with severe, poorly controlled hypertension had renal artery stenosis, compared with 8% of young hypertensive controls and 3% of healthy subjects. Renal artery stenosis in patients who are aPL-positive has two unique patterns: The stenosis is smooth, well delineated, often non-critical, localized distal to the renal artery ostium, and a less frequent pattern is localized proximally, occasionally involving the aorta. The most common clinical presentation of renal artery thrombosis is the sudden onset of severe hypertension or worsening of pre-existing systemic hypertension, sometimes accompanied by flank pain, hematuria, or renal failure. The underlying pathogenesis may involve in situ thrombosis of the renal arteries or embolization from verrucous heart valve lesions. The occurrence of renal artery thrombosis in patients with SLE with positive aPLs, as well as in those with SLE-related APS or PAPS, suggests a likely pathophysiological association with aPLs[44].

Renal vein thrombosis

Asherson et al[42] first described renal vein thrombosis in 2 patients with SLE with proliferative LN and LA. D'Cruz et al[45] suggested that aPLs play an important role in the development of renal vein thrombosis. Glueck et al[46] reported renal vein thrombosis in 3 of 18 patients with SLE with LA, whereas none of the 59 patients with SLE without LA exhibited this finding. The clinical presentation of renal vein thrombosis varies depending on the extent of the lesion, with nephrotic-range proteinuria being the most common manifestation. Renal failure may also develop, particularly in cases involving bilateral renal vein thrombosis. It is indicated that any patient with APS, who develops sudden nephrotic-range proteinuria, should be carefully evaluated by imaging methods to rule out renal vein thrombosis[11].

APSN

Intrarenal vascular lesions associated with APS define APSN. APSN is defined as vascular lesions (total or partial) characterized by acute thrombosis and/or chronic arterial and or arteriolar lesions in patients with aPLs. APSN can manifest as a broad spectrum of clinical features, ranging from isolated arterial hypertension to microscopic hematuria, proteinuria (which may vary from mild to nephrotic levels), acute kidney injury, or a slowly progressive form of chronic kidney disease. APSN has been detected in patients with both PAPS and secondary APS and patients with non-APS lupus positive for aPLs at significantly higher rates than in patients with SLE who are negative for aPLs[12,39,46]. Systemic hypertension is the most common presenting feature of APSN, along with decreased glomerular filtration rate[40]. Heavy proteinuria is uncommon in the chronic form of APSN because most patients present with proteinuria less than 1.5 g/d[47]. APSN was first recognized as a distinct clinical and histopathological entity in 1999[36]. TMA is the hallmark histological feature of the acute form of APSN, characterized by the presence of fibrin microthrombi within arterioles, small arteries, and/or glomerular capillaries. Cellular proliferation, inflammation, and immune complex deposits on immunofluorescence are absent in primary APSN. In secondary forms of APSN associated with SLE, lupus glomerulonephritis may occur concurrently[48]. Chronic APSN lesions represent a continuum of persistent thrombotic damage and subsequent scarring, characterized by arteriosclerosis, intimal hyperplasia of the vascular wall, fibrous arterial occlusion, focal cortical atrophy (FCA), arteriolar vaso-occlusive changes, and tubular thyroidization[11] (Figure 2). Nochy et al[22], after analyzing 16 renal biopsies from patients with PAPS, proposed that the diagnosis of APSN requires the presence of at least one of the following lesions: Thrombotic microangiopathy (acute lesion), interlobular fibrous intimal hyperplasia, arterial or arteriolar recanalizing thrombi, fibrous arterial occlusion, or FCA.

Figure 2 Morphological features of chronic antiphospholipid syndrome nephropathy. A: Low-power view showing subcapsular focal cortical atrophy, a characteristic lesion of chronic antiphospholipid syndrome nephropathy (APSN) (hematoxylin & eosin, 100 ×); B: Low magnification view showing the same lesion on trichrome stain (Masson’s trichrome, 100 ×); C: Another biopsy with chronic APSN showing ischemic solidification of some glomeruli as a result of chronic ischemia (Periodic acid-Schiff [PAS], 200 ×); D: Another area from the latter biopsy showing fibrous intimal thickening observed in chronic forms of APSN (PAS, 200 ×).

Ultrastructurally, a combination of glomerular basement membrane wrinkling and reduplication may be seen[49-51]. Tektonidou and coworkers showed that in LN biopsy samples, APSN lesions were much more prevalent in patients who were aPL-positive compared to those who were aPL-negative (39.5% vs 4.3%). APSN was found in two-thirds of those meeting APS criteria. APSN was associated with a higher incidence of hypertension and elevated serum creatinine levels; however, it did not predict an increased risk of renal function decline, progression to end-stage renal disease (ESRD), or mortality at the end of follow-up[12]. The same group examined three different APS groups for acute and chronic APSN lesions: PAPS, secondary APS, and CAPS. In the context of TMA, acute lesions were more frequently seen in CAPS, whereas the prevalence of chronic lesions like tubular atrophy and interstitial fibrosis was similar in all three groups[52]. Cheunsuchon et al[53], reported APSN lesions in 34% of 150 patients with biopsy-proven LN. APSN was associated with more severe hypertension, acute renal failure, persistent heavy proteinuria, severe LN class III and IV, and ESRD. In a Spanish cohort of 77 patients with SLE with biopsy-confirmed renal involvement, a significant association was observed between APSN and the presence of aPLs (P = 0.003), particularly in patients with both LA and IgG aCLs (OR: 3.61, P = 0.002). Serum creatinine levels were notably higher in patients with APSN (P = 0.038); however, there were no significant differences between groups in terms of complete or partial remission rates, lack of response, or the extent of chronic renal damage[54].

PATHOGENESIS OF APSN

APSN is a distinct renal vascular pathology observed in patients with APS, encompassing both primary and secondary forms of the disease. APSN is characterized by acute or chronic vaso-occlusive lesions affecting small and medium-sized renal vessels, leading to a spectrum of clinical manifestations including hypertension, proteinuria, hematuria, and progressive renal dysfunction. The pathogenesis of APSN reflects the broader immunothrombotic mechanisms that underpin APS, wherein aPLs promote a proinflammatory and prothrombotic state within the renal microvasculature. The development of APSN is best explained by a two-hit hypothesis, which combines autoimmune factors with prothrombotic mechanisms. In the first hit, the initial event involves a prothrombotic state driven by the presence of aPLs attributed to their interaction with plasma coagulation regulatory proteins and their ability to activate cells like platelets, monocytes, and endothelial cells[55]. This creates a hypercoagulable and pro-inflammatory environment within the renal microvasculature. In the second hit, triggering events such as infections, surgery, trauma, pregnancy, hypertension, or immune activation (e.g, SLE flare) play a key role in initiating thrombus formation (Figure 3). These lead to activation of classical and alternative complement pathways, amplifying vascular injury and thrombosis[56].

Figure 3 Pathogenesis of antiphospholipid syndrome: The dual hit theory explained. Schematic representation of the two-hit theory in antiphospholipid syndrome-mediated renal injury. “First hit” involves the presence of antiphospholipid antibodies in the circulation. “Second hit” refers to any triggering event that leads to thrombus formation when circulating antiphospholipid antibodies bind to β2 glycoprotein I (B2GPI), triggering complement activation, recruitment of inflammatory cells, and thrombus formation.

Role of aPLs

The pathogenic hallmark of APS lies in the presence of circulating aPLs, particularly LA, aCLs, and anti-β₂GPI. These autoantibodies target phospholipid-binding proteins on endothelial cells, monocytes, and platelets, initiating a cascade of cellular activation events. Binding of aPLs to β2GPI expressed on renal endothelial surfaces triggers the upregulation of adhesion molecules (e.g., vascular cell adhesion protein 1 [VCAM-1], intercellular adhesion molecule 1 [ICAM-1]), release of pro-inflammatory cytokines (e.g., interleukin 6, tumor necrosis factor alpha [TNF-α]), and increased expression of tissue factor (TF), which collectively drive localized thrombogenesis[57].

Endothelial cells, monocyte activation, and injury

Endothelial cell dysfunction is a central feature in APSN pathogenesis. Upon exposure to aPLs, renal endothelial cells adopt a procoagulant and proadhesive phenotype[58]. In vitro studies have demonstrated that anti-β2GPI antibodies enhance TF expression and reduce thrombomodulin expression on endothelial surfaces, tipping the balance towards coagulation[59]. β2GPI autoantibodies stimulate monocytes to increase TF expression and TNF-α[60]. aPL autoantibody-induced TF expression is mediated through a number of intracellular signaling pathways[61]. Autoantibodies from patients with APS can disrupt the mitochondrial function of monocytes and neutrophils, leading to the generation of various intracellular reactive oxygen species by means of nicotinamide adenine dinucleotide phosphate, oxidase activation, and the subsequent expression of TF[62]. aPL binding to β2GPI on endothelial cells trigger cell activation through Toll-like receptors and other pathways, including p38 mitogen-activated protein kinase and nuclear factor kappa B signaling. This results in the expression of adhesion molecules, TF, and a reduction in the production of nitric oxide (NO). NO deficiency causes impaired vasodilation and promotes platelet adhesion to the endothelium, contributing to a prothrombotic vascular environment. aPL-induced oxidative stress and NO depletion further compromise endothelial integrity, promoting vascular occlusion and ischemia in the renal parenchyma[56,63].

Complement activation

Emerging evidence highlights the pivotal role of the complement system in amplifying aPL-mediated injury. Activation of both the classical and alternative complement pathways has been implicated in APS, particularly in CAPS and renal involvement. Activation of complement components such as C3a and C5a promotes leukocyte recruitment, endothelial activation, and amplification of thrombosis. C5a, a potent anaphylatoxin, recruits and activates neutrophils and monocytes, thereby enhancing endothelial cell damage and thrombosis[64]. C5a, in particular, has been shown to promote neutrophil extracellular trap (NET) formation, a process known as NETosis. These web-like structures, composed of DNA, histones, and proteolytic enzymes (e.g., neutrophil elastase, myeloperoxidase), trap pathogens but also promote thrombosis by activating platelets and coagulation factors, providing a scaffold for fibrin deposition, damaging the endothelium, and reducing its anticoagulant properties. Activated neutrophils and NETs contribute to endothelial cell activation, upregulating adhesion molecules (e.g., ICAM-1, VCAM-1) and TF expression on monocytes, both of which contribute to thrombus formation. Adhesion molecules on endothelial cells facilitate leukocyte recruitment and vascular injury[65]. Complement deposition, especially C4d and C5b-9, has been demonstrated in renal biopsy specimens from patients with APSN, supporting its direct involvement in vascular injury[66].

TMA and vascular lesions

Histopathologically, APSN is defined by the presence of both acute and chronic vascular lesions. Acute changes include TMA, characterized by fibrin thrombi in glomerular capillaries and arterioles without significant inflammatory infiltrate. Chronic lesions include fibrous intimal hyperplasia, organized thrombi with recanalization, FCA, and arteriosclerosis. These changes lead to chronic ischemia, glomerulosclerosis, and ultimately interstitial fibrosis and tubular atrophy, contributing to progressive renal impairment[38].

Interaction with secondary autoimmunity

In patients with SLE, the coexistence of APS and LN complicates renal pathology. aPLs exacerbate vascular inflammation and promote thrombotic complications even in the setting of immune complex-mediated glomerulonephritis. Moreover, corticosteroid and immunosuppressive treatment may mask the inflammatory component, making vascular lesions more prominent in biopsy samples[12].

ESRD

In patients with ESRD on maintenance hemodialysis, a high prevalence of aPL has been reported in comparison to the general population[67-70]. The prevalence of LA was higher among patients undergoing hemodialysis (30%) compared with those managed conservatively (non-dialytic approach)[71]. This higher prevalence in hemodialysis has been confirmed by others[70]. The presence of aPLs was shown to be independent of factors such as age, sex, duration of dialysis, type of dialysis membrane, medication use, and chronic hepatitis B or C infection[70,72]. The underlying cause of APS in patients with ESRD remains uncertain. It has been proposed that uremia represents a state of immunodeficiency in which autoimmune processes may arise due to impaired immune regulation[72].

Some investigators have proposed that dialysis membranes may induce the formation of aPLs due to biocompatibility issues. In a study by Garcia-Morton et al[70], patients undergoing dialysis with cuprophane membranes showed a higher incidence of APS compared to those treated with more biocompatible membranes. However, a larger study by Brunet et al[72] found no association between APS and the type of dialyzer used. Other proposed mechanisms for the development of aPLs in patients with ESRD include mechanical trauma to blood as it circulates through the hemodialysis circuit, similar to what is observed in recipients of left ventricular assist devices, and stimulation by microbial agents or their products, such as endotoxins present in the dialysate[73]. If this hypothesis is correct, a correlation would be expected between the prevalence or titers of aPLs and the duration of dialysis; however, such a relationship has not been demonstrated. Furthermore, not all patients exposed to the same dialysate develop APS. The clinical significance of aPLs in patients undergoing hemodialysis remains unclear; while some studies consider them non-pathogenic, others have reported an association between aPLs and vascular access thrombosis in these patients[74-81]. Some studies have suggested both aCL and LA as risk factors in causing recurrent access thrombosis, while others only LA[78,79].

Renal transplant

APSN presents a unique challenge in renal transplantation due to its association with TMA, recurrent vascular lesions, and heightened risk of graft failure. The role of aPLs in graft failure has been investigated in a number of studies. There is growing and compelling evidence that renal allograft recipients who are aPL-positive face a persistently high risk of thromboembolic complications during the post-transplant period[82-85]. This risk is especially pronounced during the first week after transplantation, a period marked by a notably higher incidence of renal vein thrombosis[86-90]. Wagenknecht et al[85] reported a significantly higher prevalence of aPLs in patients with early renal allograft failure compared to those with functioning grafts. In that study, 57% of patients with early nonfunctioning grafts tested positive for IgG, IgM, and IgA aPLs. Biopsies from failed grafts in patients who were aPL-positive revealed thrombi in 9 cases and infarction in 5 cases[85]. The presence of LA has been linked to poorer graft outcomes compared with other types of aPLs[90].

Advances in post-transplant monitoring have significantly enhanced early aPL detection, risk stratification, and management of complications in patients with APSN. Emerging biomarkers have improved the ability to detect early endothelial injury and thrombotic events. Anti-β2GPI and LA levels should be monitored regularly to assess ongoing antiphospholipid activity. Elevated levels of soluble thrombomodulin, endothelial microparticles, and complement activation fragments (C3a, C5a) may serve as indicators of microvascular injury. Urinary markers such as neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 are being explored for early tubular damage. Donor-specific antibody monitoring by luminex remains vital, as patients with APSN are prone to antibody-mediated rejection. Protocol renal biopsies at set intervals post-transplantation for early detection of chronic TMA or fibrous intimal hyperplasia, characteristic features of APSN recurrence. These tools support individualized monitoring strategies that enhance early intervention, prevent graft loss, and improve long-term graft outcomes[88-91].

CAPS

CAPS is a rare, life-threatening variant of APS characterized by widespread intravascular thrombosis leading to multiorgan ischemia and failure. It can involve virtually any organ or tissue, with the kidneys, lungs, central nervous system, heart, skin, liver, and gastrointestinal tract being most frequently affected. The most common renal manifestations of CAPS include hypertension, proteinuria, hematuria, and acute renal failure. In most cases, a triggering factor, such as infection, surgery, or certain medications, can be identified. Histologically, CAPS is defined by the presence of acute TMA. It is important to differentiate CAPS from other TMAs, including hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, and heparin-induced thrombocytopenia. The diagnostic criteria for CAPS include: (1) Involvement of three or more organs/tissues; (2) Development of manifestations in less than 1 week; (3) Histological evidence of intravascular thrombosis; and (4) Presence of aPLs on two occasions 6 weeks apart. A definite diagnosis of CAPS is made when all four diagnostic criteria are present. The diagnosis of CAPS is probable when a combination of these criteria is present. CAPS is an accelerated variant of APS, which is characterized by clots in multiple small vascular beds and leads to multiorgan failure with high mortality[92,93].

DIAGNOSIS OF THE APS

The diagnosis of APS is established based on a combination of clinical and laboratory criteria, as defined by the revised Sapporo classification criteria (updated in 2006)[94]. A definite diagnosis requires the presence of at least one clinical criterion—such as vascular thrombosis (arterial, venous, or small vessel) or pregnancy morbidity—and one laboratory criterion, confirmed on two or more occasions at least 12 weeks apart. Laboratory tests must demonstrate the persistent presence of aPLs, which include LA, aCL of IgG or IgM isotype in medium to high titer, and/or anti-β2GPI of IgG or IgM isotype. Transient positivity, particularly in the context of infections or medication use, does not fulfill diagnostic requirements. Additional testing may include coagulation studies, thrombophilia panels, and imaging when thrombotic events are suspected. It is essential to interpret results within a clinical context, as some individuals may have isolated aPL positivity without clinical manifestations (termed aPL carriers), and others may have non-criteria manifestations such as livedo reticularis, thrombocytopenia, or cardiac valvulopathy that may complicate diagnosis. APS diagnosis is based on the presence of at least one clinical and one laboratory criteria. The clinical and laboratory criteria for the diagnosis of APS are shown in Table 2. However, over time, many shortcomings were noted in these criteria. For example, these do not adequately recognize the differences between IgG and IgM (IgG autoantibodies are closely associated with thrombotic APS, whereas IgM is with obstetric APS). These did not emphasize late vs early-pregnancy morbidities, and there was a lack of recognition of microvascular clotting manifestations, along with other laboratory or imaging clues for APS. Non-criteria manifestations—such as thrombocytopenia, livedo reticularis, heart valve disease, and neurological features-were excluded despite their strong association with APS, potentially resulting in missed diagnoses. The Sydney criteria required persistent positivity for aPLs at least 12 weeks apart, which may delay diagnosis and treatment in high-risk patients. Additionally, the criteria focused only on three types of aPLs (LA, aCL, anti-β2GPI), excluding other potentially relevant antibodies like anti-phosphatidylserine/prothrombin. These limitations underscore the need for updated criteria that incorporate evolving clinical understanding and laboratory advances in APS.

Table 2 2006 Revised Sapporo criteria for antiphospholipid syndrome (also called the Sydney criteria).

Clinical criteria	Laboratory criteria
One or more of the following is present:	The presence of one or more of the following aPLs on two or more occasions at least 12 weeks apart
(1) Vascular thrombosis	IgG and/or IgM aCLs in moderate or high titer (> 40 GPL or MPL units, respectively, or a titer > 99th percentile for the testing laboratory), measured by a standardized enzyme-linked immunosorbent assay
One or more episodes of venous, arterial, or small vessel thrombosis in any tissue or organ
(2) Pregnancy morbidity	IgG and/or IgM anti-2 glycoprotein I > 40 GPL or MPL units, respectively, or a titer > 99th percentile for the testing laboratory, measured by a standardized ELISA according to recommended procedures
(a) One or more unexplained deaths of a morphologically normal fetus at ≥ 10 weeks gestation; (b) One or more premature births of a morphologically normal neonate before 34 weeks gestation because of eclampsia, preeclampsia, or placental insufficiency; and (c) Three or more consecutive spontaneous pregnancy losses at < 10 weeks gestation with maternal and paternal factors (anatomic normal and chromosomal abnormalities excluded)
	Lupus anticoagulant present in plasma, on 2 or more occasions at least 12 weeks apart

aCLs: Anticardiolipin antibodies; aPL: Antiphospholipid antibodies; ELISA: Enzyme-linked immunosorbent assay; GPL: IgG phospholipid units; IgG: Immunoglobulin G; IgM: Immunoglobulin M; MPL: IgM phospholipid units.

In 2023, the ACR and EULAR jointly released revised classification criteria for APS, representing a major advancement in the field of autoimmune rheumatology[95,96].

The updated criteria emphasize a more stringent and structured approach to the diagnosis of APS. To be classified as having APS under the new system, a patient must first satisfy an entry criterion: The documented presence of at least one of the three aPLs-LA, aCL, or anti-β2GPI-on two or more occasions, at least 12 weeks apart. Importantly, only medium-to-high titers of aCLs and anti-β2GPI IgG or IgM are considered valid under these criteria. Once the entry criterion is met, a weighted points scoring system is applied, integrating both clinical and laboratory domains. Points-based scoring allows for a more nuanced and flexible classification based on disease burden. Points are given to clinical features according to their significance (Table 3). Higher points are given to late pregnancy loss and arterial thrombosis, reflecting their importance. High titers and triple positivity for aPLs have been given greater weightage according to the associated risk. Hypocomplementemia and other associated markers have been included in the criteria to improve sensitivity and specificity. A total score of ≥ 10 points is required for classification. This novel point-based system aims to resolve limitations associated with the earlier Sydney (2006) criteria, particularly in distinguishing APS from related autoimmune or prothrombotic conditions. The revised criteria also include a broader range of clinical manifestations, such as microvascular thrombosis and specific non-criteria obstetric events, acknowledging the heterogeneity of APS presentations. By introducing graded weightings for different aPL profiles and clinical events, the system enhances specificity without substantially compromising sensitivity. The revised ACR/EULAR criteria represent a significant step toward improving diagnostic consistency across clinical trials and research cohorts, thereby facilitating the development of targeted therapies and improving patient outcomes. However, it is crucial to emphasize that classification criteria are not diagnostic tools and should be applied with clinical judgment. Ongoing validation in diverse populations and clinical settings will be essential to determine the utility of these criteria in routine practice. The 2023 ACR/EULAR criteria for APS mark a significant advancement over the 2006 Sydney criteria by introducing a quantitative and stratified classification approach. These new criteria aim to enhance diagnostic precision, especially in complex or atypical cases, by recognizing the variability in clinical severity and aPL risk profiles. The newly established criteria aim to improve diagnostic accuracy and patient outcomes through a more systematic and evidence-based approach[95,97,98].

Table 3 EULAR 2023 classification criteria for antiphospholipid syndrome.

(1) Entry criterion:

A patient must have at least one positive aPL test (LAC, aCL IgG/IgM, or anti-β2GPI IgG/IgM) on two occasions at least 12 weeks apart

The positive test must be from a solid-phase assay validated for clinical use, and at least one test must be high-titer or persistent

(2) Additive weighted scoring:

Once the entry criterion is met, clinical and laboratory features are assigned points

A score of ≥ 10 points is required to classify a patient as having APS

Clinical criteria

Venous thromboembolism 4 points

Arterial thrombosis 5 points

Pregnancy morbidity

≥ 3 consecutive unexplained early miscarriages 3 points

≥ 1 unexplained fetal death after 10 weeks 4 points

Preterm birth due to eclampsia/HELLP/severe 3 points preeclampsia

Laboratory criteria

LAC - 4 points

High-titer aCL IgG or anti-β2GPI IgG - 3 points

Double or triple antibody positivity - 3 points

C3/C4 (suggesting complement activation) - 2 points

Classification as APS requires a total score of ≥ 10 points, combining laboratory and clinical features

aCL: Anticardiolipin antibody; aPL: Antiphospholipid antibody; APS: Antiphospholipid syndrome; β2GPI: Β2 glycoprotein I; EULAR: European League Against Rheumatism; HELLP: Hemolysis, elevated liver enzymes, and low platelets; IgG: Immunoglobulin G; IgM: Immunoglobulin M; LAC: Lupus anticoagulant.

MANAGEMENT

Management of APSN is challenging and often requires a multidisciplinary approach, combining anticoagulation and immunosuppression in patients with coexisting LN or CAPS and managing associated comorbidities. Management of APSN is largely based on expert consensus due to the lack of randomized trials. Lifelong anticoagulation is the mainstay of treatment for patients with APSN and thrombotic events. Vitamin K antagonists (VKAs), mainly warfarin, targeting an INR of 2.0-3.0 are recommended. In cases with recurrent thrombosis, a higher INR target (3.0-4.0) may be needed[1].

Two randomized clinical trials compared warfarin at an INR target range of 2.0-3.0 vs 3.0-4.0 in patients with APS. Both trials concluded that there was no benefit to a higher therapeutic target INR[99,100].

Rivaroxaban, a direct oral anticoagulant (DOAC) that inhibits factor Xa, has been evaluated as an alternative to traditional VKAs like warfarin in the management of APS. In a multicenter randomized trial comparing rivaroxaban vs warfarin in patients with high-risk APS (triple-positive for LA, aCL, anti-β2GPI), a higher rate of thrombotic events in the rivaroxaban group was observed compared to the warfarin group[101].

EULAR 2019 and ASH 2020 guidelines recommend against DOACs in high-risk APS, particularly in patients with triple positivity, those with arterial thrombosis, and patients with recurrent thrombosis on anticoagulation[1,102].

Antiplatelet therapy (e.g., low-dose aspirin) may be added in selected patients, especially with arterial involvement or high cardiovascular risk.

Aggressive blood pressure control is crucial to prevent further renal damage[103].

Renin-angiotensin-aldosterone system blockade with angiotensin-converting enzyme inhibitors represents first-line drugs used to reduce proteinuria and slow the progression of renal damage[104].

Hydroxychloroquine (HCQ), a well-established antimalarial and immunomodulatory agent, has been increasingly recognized for its potential benefits in patients with APS, including those with APSN. APSN may coexist with LN or other autoimmune renal lesions in secondary APS. HCQ may benefit patients with SLE-associated APSN, particularly due to its antithrombotic, endothelial-protective, and immunomodulatory properties[11,105].

In a study by Dima et al[106], patients with PAPS treated with HCQ had a lower rate of thrombosis recurrence compared to those not receiving HCQ.

Immunosuppressive treatment, including corticosteroids, cyclophosphamide, or mycophenolate mofetil is indicated in APS. De Simone et al[107] reported that immunosuppressive therapy prescribed for LN has shown little efficacy on thrombotic events in patients with APS.

Rituximab represents a promising off-label option for APSN and has been considered in refractory cases, where it may help reduce the production of pathogenic autoantibodies. Its ability to deplete B cells has shown potential benefits in reducing disease activity, controlling systemic manifestations, and possibly improving renal function in selected patients with APSN. Case reports and small observational studies have documented favorable outcomes with rituximab in patients with APS who had resistant nephropathy or an overlapping autoimmune condition[108-112].

A single-center cohort of SLEassociated APS involving 6 patients treated with rituximab showed no further thrombotic events over an average 39-month follow-up and reduced SLE disease activity[113].

Belimumab, a B-cell activating factor antagonist, has been used in 2 cases with PAPS, 1 with recurrent alveolar hemorrhage and 1 with recurrent skin ulcers. Both patients had clinical improvement and were able to discontinue corticosteroids[114].

The mammalian target of rapamycin (mTOR) pathway plays a central role in cell proliferation, survival, and immune regulation. Dysregulation of this pathway has been implicated in the pathogenesis of vascular injury and fibrosis, both key features of APSN. mTOR inhibitors, such as sirolimus, have emerged as potential therapeutic agents for APSN due to their immunomodulatory, antiproliferative, and antifibrotic properties.

In APSN, the deposition of aPLs leads to endothelial cell activation, complement activation, and thrombotic microangiopathy, contributing to chronic vascular lesions. Studies have shown that aPLs can activate the mTOR pathway, promoting proinflammatory and procoagulant phenotypes in endothelial cells and monocytes. By inhibiting mTOR signaling, sirolimus may mitigate endothelial dysfunction and reduce vascular injury in APSN[112,115].

Sirolimus has shown benefit in preventing the recurrence of APSN and TMA in renal allografts. Ponticelli[116] documented improved graft survival and stabilization of renal function when sirolimus was used instead of calcineurin inhibitors, which can exacerbate vascular lesions.

Eculizumab, a membrane attack complex inhibitor, plays an important role in managing TMA. Eculizumab is effective for the treatment and prevention of APS relapses in kidney transplant recipients[117].

Strict control of hypertension, diabetes, and dyslipidemia is essential in reducing vascular complications. Smoking cessation, lipid control, weight management, and avoidance of estrogen-containing contraceptives are essential in long-term care. APSN may lead to ESRD. Hemodialysis or peritoneal dialysis is initiated as needed. Kidney transplantation is feasible but requires careful perioperative anticoagulation to prevent graft thrombosis.

CONCLUSION

APS represents a complex autoimmune disorder with significant renal implications, most notably in the form of APSN. The presence of aPLs such as aCLs, anti-β2GPI, and LA plays a central role in the pathogenesis and diagnosis of the syndrome. Renal involvement, ranging from large-vessel thrombosis to microvascular injury, contributes substantially to morbidity, especially in both native and transplanted kidneys. Despite advances in our understanding, the diagnostic and risk stratification criteria for APS and APSN remain areas of ongoing research and refinement. This review highlights the need for heightened clinical awareness, early recognition of renal involvement, and multidisciplinary approaches for accurate diagnosis and individualized management. Continued research into the pathogenic mechanisms and biomarkers is essential to improve outcomes in patients with APS and its renal manifestations.