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Written by: Susan Thanabalasingam, MD
Infographic by: Corina Teodosiu, MD
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.
‘‘With this clinical scenario there’s just one thing this could be
But you have so many symptoms we must list them carefully
You have swollen limbs and migraine and livedo – that makes three
Not to mention all your chest pain and your shortening of breath
Which is probably a PE if you want to take the test
It’s a classic combination so there is no need to guess
For I’m certain that the diagnosis must be APS!’’
(Rahman, 2010, Poem: The appropriate management of the antiphospholipid syndrome in extra-terrestrials)
If only the royal English physicians of the 1700’s had read this poem about a certain alien’s affliction, the British monarchy might have looked altogether different today. Queen Anne was plagued with multiple health issues throughout her life, including a fatal stroke, and prior to that, over a dozen miscarriages that ultimately meant the Crown was passed from the house of Stuart to the house of Hanover, whose descendants currently occupy the throne (Weissmann, 2014). Today, we recognize these symptoms as pathognomonic of antiphospholipid antibody syndrome (APS), a systemic autoimmune disorder characterized by recurrent arterial and venous thrombosis and/or pregnancy loss in the setting of the persistent antibodies against phospholipid-binding proteins. APS is among the most common acquired thrombophilias, with an estimated prevalence of 40-50 cases per 100 000 (Dabit, 2021). Although the lower limb deep vein system and the cerebral arterial circulation are the most common sites of thrombosis, any tissue or organ may be affected by this disease (Chaturvedi, 2017).
The APS diagnostic criteria were initially established in 1998, and subsequentlyrevised in 2006. A minimum of 1 clinical and 1 laboratory criteria are required to establish a diagnosis.
Infographic by @CTeodosiu
When APS is diagnosed in the setting of other autoimmune conditions, namely systemic lupus erythematosus (SLE), it is termed secondary APS. In the absence of other autoimmune conditions, it is termed primary APS (PAPS).
The pathogenesis of circulating APS appears to require circulating aPLs and endothelial dysfunction, which in conjunction, promote thrombosis and platelet aggregation. The endothelial dysfunction is thought to be a product of circulating aPLs binding to 𝛃2-GP1 receptors on the surface of endothelial cells. Endothelium-derived nitric oxide (NO) is also important for normal endothelial cells due to its antithrombotic function. aPLs have been associated with inhibition of NO, which likely plays an important role in increasing thrombosis risk in APS. Pro-inflammatory states, such as surgery, infection, or trauma also seem to further promote thrombotic events in APS by upregulating the expression of 𝛃2-GP1 receptors. Endothelial dysfunction induced by aPLs has also been associated with vasculopathy, namely diffuse intimal hyperplasia, accelerated atherosclerosis and coronary microvascular obstruction. Finally, activation of the classical complement pathway has also been implicated as a thrombogenic effect of circulating aPLs.
Can APS affect the kidney? Although renal involvement is less common. APS can affect diverse aspects of the kidney vasculature, including arteries and veins, intrarenal arteries and arterioles, and glomerular capillaries (Tektonidou, 2018). A wide spectrum of kidney lesions associated with antiphospholipid antibodies (aPLs) have been identified on kidney biopsy since the 1990s (Amigo, 1992; Nochy, 1999). Kidney involvement in patients with circulating anti-phospholipid antibodies (aPL) has been historically referred to as “APS nephropathy” (APSN), although this term is broadly used to cover a collection of heterogeneous lesions and manifestations. Although we have known about kidney involvement in APS for several decades, the clinical significance of these aPL-related kidney lesions remains unclear.
This brings us to the present study: “Clinical-pathological characteristics of renal injuries identify different clusters in patients with antiphospholipid antibodies,” published in KI reports earlier this year (Sciascia, 2023). This study aimed to identify subgroups of patients with circulating aPLs and biopsy-proven kidney involvement according to clinical, laboratory and histologic characteristics using hierarchical cluster analysis. Their secondary aim was to determine if these subgroups conferred any prognostic utility with respect to kidney outcomes.
Visual abstract by @jmteakell
Participants were recruited from centers in Italy, the United States, the United Kingdom, and Brazil. Medical records from 2011-2021 were screened to identify eligible participants. Inclusion criteria were:
Adults > 18 years old
aPL positivity confirmed 12 weeks apart
Kidney biopsy performed due to suspected kidney involvement based on any of:
nephrotic-range proteinuria
active urinary sediment
hematuria and non-nephrotic range proteinuria
acute worsening of kidney function
Histological aPL-related kidney injuries were classified into acute and chronic lesions and categorized using an a priori defined data collection approach. Pathology reports were reviewed centrally for consistency.
Kidney outcomes were assessed at 12 months and classified as:
Complete renal response, defined as return to baseline SCr + decline in uPCR to <500 mg/g (50 mg/mmol).
Partial renal response, defined as SCr stabilization or improvement + ⩾50% decrease in uPCR.
No renal response, defined as sustained 25% increase in SCr, increase in proteinuria, or reduction in proteinuria not to the extent of complete or partial response.
Ultimately, 123 patients (82% female) were included in the analysis. Forty-one (33%) patients had an established diagnosis of APS and 14 patients had PAPS. Most of the cohort had SLE (n=109, 89%), of whom 27 (22%) met criteria for secondary APS. A minority of the cohort (n=21, 20%) patients had triple aPL antibody positivity. In terms of renal function, thirty-one (30%) of the cohort had a serum creatinine > 3 mg/dL, 81 (79%) patients had microscopic hematuria, and 52 (51%) patients had proteinuria > 3.5 g/day. With respect to treatments, 59% of the cohort was on RAS blockade, 72% on aspirin and 29% on vitamin K antagonists. Among those patients who received induction therapy for lupus nephritis, 60% received mycophenolate mofetil, 34% received cyclophosphamide and 29% received the EUROLUPUS regimen. Hydroxychloroquine use was not outlined in the cohort characteristics.
Histological Results
Subendothelial edema (64%) was the most common acute glomerular lesion identified on histology while fragmented RBCs in the subendothelial space and intimal layers was the most common acute lesion in arteries and arterioles. Chronic lesions were most often characterized by capillary wall thickening with double contours, while fibromyointimal proliferation with luminal narrowing was most often observed in arteries and arterioles.
Cluster Analysis
Cluster 1 (n = 23, 19%)
Termed ‘TMA’ (thrombotic microangiopathy) because as in acute TMA, there was a higher prevalence of capillary and arteriolar thrombi and fragmented RBCs in the subendothelial space
Likewise, as in chronic TMA, there was also capillary wall thickening with double contours, organizing thrombi and ischemic collapse of the glomerular tuft due to afferent arterial occlusion.
Notably, there was markedly higher prevalence of thrombotic events (n = 26), aGAPSS > 12 (higher score corresponds to greater recurrent thrombosis risk), and triple aPL positivity in this cluster.
This cluster included 18 patients with SLE and 5 patients with PAPS.
Cluster 2 (n = 33, 27%):
Termed ‘Hyperplastic Vasculopathy’ as there was a higher prevalence of fibromyointimal proliferation (‘onion-layering’) with luminal narrowing in this cluster.
There was a higher prevalence of CVA (TIA and stroke) in this cluster (n=7).
This cluster included 24 patients with SLE and 9 patients with PAPS.
Cluster 3 (n = 67, 54%)
Termed ‘Subendothelial Edema’ as this cluster had a higher prevalence of subendothelial edema in the glomerular capillaries and in the arterioles.
There were no overt associations with thrombotic events in this cluster.
All 67 patients had SLE in this cluster.
Prognosis
Cluster 1 (‘TMA’) was associated with the poorest renal prognosis, while patients in cluster 3 (‘Subendothelial Edema’, all of which had concurrent SLE) had the highest rate of complete renal response. The poor renal prognosis in cluster 1 is consistent with previous studies (Wu, 2013; Song, 2013) that identified the presence of TMA as a poor prognostic indicator. The alternative complement pathway has been implicated in aPL-related thrombotic lesions, with recent evidence demonstrating therapeutic success with eculizumab (antibody against c5) with demonstrably rapid improvement of TMA lesions. With cluster 1 having the highest prevalence of patients with thrombotic APS, the authors speculate as to whether patients in Cluster 1 may be the most representative of ‘true’ APSN.
Notably, all patients in cluster 3 had SLE or LN, with low rates of APS. Given this, and that subendothelial edema is considered an acute reaction to endothelial injury, the authors speculate whether this lesion is an early form of TMA or non-specific for aPL injury, perhaps instead belonging to the lupus nephritis spectrum. If subendothelial edema is in fact an earlier lesion, it is also plausible that there is potential for reversibility with interventions like immunosuppressive therapy.
Cluster 2 ‘Hyperplastic Vasculopathy’ had a renal response profile between that of clusters 1 and 3. There were few patients with APS and few thrombotic events in this cluster, suggesting the pathophysiology be distinct from Clusters 1 and 3. Recent work has suggested that hyperplastic lesions may be complement-independent, instead associated with the mTOR pathway. Previous examination of kidney transplant patients with circulating aPL antibodies demonstrated that those managed with sirolimus for immunosuppression had decreased vascular proliferation on biopsy and better allograft function at 12 months compared to those not receiving sirolimus. Given the pathophysiological difference between these clusters, the authors suggest that patients fitting the cluster 2 phenotype could be referred to as aPL-related vasculopathy, rather than APSN.
The authors identified several limitations including potential inclusion bias with the retrospective nature of the study and the inability to examine the independent effect of LN on the aPL related pattern of injuries when APSN occurred in the setting of co-existing LN.
In this study, Sciascia and colleagues provide us with an exciting new paradigm for understanding aPL-related kidney disease based on histopathological and clinical characteristics. Rather than lumping all kidney pathology in the context of circulating aPL into one box, this study identifies specific patterns of kidney disease, each with potentially different prognoses and treatment courses. This was ultimately a small, retrospective study and further studies to validate the proposed clusters, including prospective investigations, will be important next steps.
This study could potentially shift how we frame the paradigm of managing aPL related renal injuries. In the absence of clear guidelines for management of these patients, the present study offers the possibility of individualizing treatment according to findings on biopsy. Patients in cluster 1, with TMA lesions that may involve the alternate complement pathway could potentially benefit from eculizumab. Those in cluster 2, with complement-independent hyperplastic vasculopathy lesions may benefit from targeting the mTOR pathway with inhibitors such as sirolimus. Patients with subendothelial edema (cluster 3) lesions on biopsy may respond to immunosuppressive therapy used in the management of lupus nephritis such as steroids, mycophenolate mofetil or cyclophosphamide. While examining different therapeutic options based on the histopathology and proposed pathophysiology of the observed lesions was outside the scope of this study, the clusters of aPL-related kidney injury identified here excitingly may indeed help direct future research in this area.
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.