Perspective on Renal Involvement in Antiphospholipid Syndrome: Implications for Diagnosis, Pathogenesis, and Treatment

Abstract

Antiphospholipid syndrome (APS) can affect the kidneys, leading to renal artery and vein thrombosis, allograft loss following transplantation, and microvascular damage referred to as aPL-nephropathy (aPL-N). APL-N is a complex and frequently underdiagnosed condition characterized by an incomplete understanding of its etiopathogenesis and associated with unfavorable renal outcomes. The 2023 ACR/EULAR classification criteria for APS included aPL-N within the microvascular domain. The gold standard for aPL-N is the biopsy, revealing lesions associated with acute thrombotic microangiopathy and chronic vascular changes. Nevertheless, reluctance for biopsies due to anticoagulation and thrombocytopenia underscores the need for noninvasive diagnostics. Common clinical features include hypertension, microscopic hematuria, proteinuria, and renal insufficiency. Antiphospholipid antibodies seem crucial to kidney damage through thrombotic and inflammatory processes. Studies and experimental models of thrombotic microangiopathy lesions suggest the involvement of the complement cascade, tissue factor, and mammalian target of the rapamycin complex activation pathway. Currently, the management of aPL-N is based mainly on expert opinion, with limited evidence supporting the use of anticoagulants, leading to controversy in their application. Treatment may include heparin, intravenous immunoglobulin, plasma exchange, and targeted therapies tailored to aPL-N mechanisms. Future multicenter studies are essential to clarify their roles. The goal of this review is to inform clinicians and create a research agenda to address the unmet needs in diagnosing and managing APL-N.

Keywords: aPL-nephropathy; antiphospholipid antibodies; lupus anticoagulant; thrombosis; thrombotic angiopathy.

Figure 1

Potential pathogenesis of antiphospholipid antibody nephropathy and possible pathway inhibitors. (A) Kidney vasculature. (B) The pathophysiology of APS is explained by the “two-hits hypothesis”, where aPL, particularly anti-β2GPI, acts as the initial catalyst in creating a prothrombotic state. However, this alone is insufficient to cause thrombosis. A second hit, such as stasis or inflammation, results in endothelial cell damage that disrupts natural anticoagulant systems, promoting thrombosis. The endothelial cell dysfunction mediated by aPL activates endothelial cells, platelets, monocytes, and neutrophils, promoting the release of neutrophil extracellular traps and tissue factor expression and activation of the complement cascade. (C) The complement-mediated tissue factor plays a critical role in the pathogenesis of thrombotic microangiopathy in APS; thus, treatment with C5a inhibitors, alongside anticoagulation and/or antiplatelet therapies, may reduce kidney injury. (D) The activation of neutrophils by aPL leads to the release of neutrophil extracellular traps and tissue factor expression, fostering thrombus development and vascular injury. Therefore, anticoagulation and/or anti-platelet therapy may sufficiently address vascular injury. Sometimes, treatment with immunosuppressants, such as rituximab, belimumab, hydroxychloroquine, or statins that inhibit tissue factor expression, could be beneficial. (E) The aPL antibodies interact with endothelial cells via the mTOR pathway, whereby the activation of the mTOR complex stimulates the growth and proliferation of endothelial cells, contributing to the chronic vasculopathy seen in chronic APL-N lesions. Consequently, treatment with mTOR inhibitors combined with anticoagulation and/or antiplatelet therapy may help alleviate kidney injury. APS: antiphospholipid syndrome; aPL: antiphospholipid antibodies; mammalian target of rapamycin: mTOR; VKA: vitamin K-antagonist; ASA: aspirin; RTX: rituximab; BEL: belimumab; HCQ: hydroxychloroquine; NETosis: neutrophil extracellular traps; MAC: membrane attack complex; β2GPI: β2 glycoprotein I. Created with https://BioRender.com (accessed on 7 January 2025).

Figure 2

Involvement of kidney vasculature showing arterial, vein thrombosis, and microvascular lesions characterized by glomerular and arteriolar thrombosis. Created with https://BioRender.com (accessed on 7 January 2025).

Figure 3

Antiphospholipid antibody nephropathy histology. (A) (Masson’s Trichrome stain 400×, scale bar 10 μm) The glomerular loops appear prominent and fill the urinary space. In some areas, the glomerular basement membranes have a fluffy appearance. Fragmented red blood cells are present in the lumen. The mesangial spaces appear expanded with pale-staining material (mesangiolysis). (B) (Masson’s Trichrome stain 200x, scale bar 10 μm) Tubulointerstitial compartment with sclerotic lesions, interstitial fibrosis, and tubular atrophy.

Figure 4

Management algorithm of kidney damage in antiphospholipid syndrome. * New onset/refractory hypertension, glomerular proteinuria/hematuria, acute kidney failure, chronic or end-stage renal disease of unknown origin, history of SLE. ^ Medium–high titer anticardiolipin antibodies and/or anti-β2glycoprotein I IgG/IgM isotype and/or lupus anticoagulant confirmed ≥12 weeks apart. # allograft, acute kidney injury, single kidney. § Unexplained persistent: (a) new onset/deterioration hypertension; (b) proteinuria ≥ 0.5 g in 24 h urine specimen or protein/creatinine ratio ≥ 0.5 mg/mg (50 mg/mmol); (c) acute renal failure; (d) glomerular microscopic hematuria. ** INR 2–3 if associated with venous thrombosis, INR 3–4 if associated with arterial thrombosis. Created with https://BioRender.com.