Ischemic Stroke in Anti-Phospholipase A2 Receptor Antibody-Positive Primary Membranous Nephropathy: Clinical and Neuroimaging Characteristics
Primary membranous nephropathy (PMN) is the leading cause of nephrotic syndrome in adults, characterized by the presence of circulating IgG4 autoantibodies targeting the phospholipase A2 receptor (PLA2R) on podocytes. While venous thromboembolism is a well-recognized complication of nephrotic syndrome, arterial thromboembolic events, including ischemic stroke (IS), are rare. This study investigates the clinical and neuroimaging features of IS in patients with anti-PLA2R antibody-positive PMN, aiming to elucidate the relationship between IS and the autoimmune renal disease.
Patient Cohort and Diagnostic Criteria
The study included 12 patients diagnosed with both IS and anti-PLA2R antibody-positive PMN at Peking University First Hospital between 2015 and 2018. All patients met clinical diagnostic criteria for PMN and tested positive for serum anti-PLA2R antibodies via enzyme-linked immunosorbent assay (ELISA). Eight patients had histopathological confirmation of PMN, and PLA2R deposition in glomeruli was verified through immunofluorescence assays. Ischemic stroke was confirmed using cranial magnetic resonance imaging (MRI), with lesions identified via diffusion-weighted imaging (DWI).
Clinical Characteristics and Risk Factors
The cohort had a mean age of 59.9 ± 12.2 years at the onset of IS. Hypertension (10/12), dyslipidemia (9/12), and smoking (6/12) were prevalent risk factors. Hypoalbuminemia (<3.5 g/dL) was observed in 9/12 patients, reflecting nephrotic-range proteinuria. Elevated D-dimer levels, indicative of a hypercoagulable state, were noted in 8/12 cases. Autoimmune profiling revealed antinuclear antibodies (ANA) positivity in only one patient (1:100 titer), ruling out systemic vasculitis or connective tissue diseases as contributors to IS.
Stroke Etiology and Classification
Using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria, stroke etiology was classified:
- Small artery occlusion (SAO): 11/12 patients had lacunar infarcts, typically in subcortical regions.
- Non-cardiac embolism: 6/12 patients exhibited multi-territory infarcts, attributed to the hypercoagulable state from PMN.
- Large artery atherosclerosis (LAA): 3/12 patients had significant arterial stenosis.
- Undetermined etiology: 3/12 cases due to incomplete vascular evaluations.
No cardioembolic sources were identified despite normal echocardiograms and Holter monitoring.
Neuroimaging Findings
MRI revealed distinct patterns of cerebral injury:
- Infarct distribution: Subcortical regions were universally affected, with frontal lobe involvement in 11/12, parieto-occipital in 8/12, and temporal lobes in 7/12. Additional lesions included basal ganglia (5/12), periventricular zones (5/12), brainstem/cerebellum (4/12), and corpus callosum (2/12).
- Lacunar infarcts: Patients had 0–16 lacunes (mean 4.5 ± 5.0), though no correlation was found between lacune count and anti-PLA2R antibody levels (Spearman r = -0.575, P = 0.064).
- White matter changes (WMC): Evaluated using the Age-Related White Matter Change (ARWMC) scale, 11/12 patients exhibited WMC. Subcortical WMC was universal, with frontal lobe involvement in 11/12, parieto-occipital in 7/12, and temporal lobes in 7/12. Global ARWMC scores ranged from 1 to 14 (mean 7.8 ± 5.0), with 45% scoring 3 (severe WMC). ARWMC severity did not correlate with anti-PLA2R titers (Spearman r = 0.152, P = 0.655).
Recurrent Stroke and Prognosis
Two patients experienced recurrent IS:
- Patient 1: Recurrence within 2 months of initial stroke despite dabigatran therapy, with new infarcts in the periventricular region and corpus callosum.
- Patient 4: Recurrence at 4 months post-stroke.
At 12-month follow-up, none of the six evaluated patients achieved complete remission (proteinuria <0.3 g/24h), and only one achieved partial remission (<3.5 g/24h). Compared to general PMN populations, IS patients had lower remission rates (16.7% vs. 58.2%) and higher recurrence rates (16.7% vs. 8.7%), suggesting IS may signal refractory renal disease.
Anti-PLA2R Antibody Levels and Implications
Mean serum anti-PLA2R antibody levels were 97.3 ± 81.0 RU/mL (range: 21–279 RU/mL). Notably, 12/14 PMN patients with IS were anti-PLA2R positive, exceeding the 58.8% seropositivity rate in the hospital’s general PMN cohort. This implicates high anti-PLA2R titers as a potential risk factor for IS, possibly through immune-mediated endothelial injury or hypercoagulability. Patients with embolic strokes (median 88.5 RU/mL) and LAA (84.0 RU/mL) had comparable antibody levels, suggesting antibody burden alone may not dictate stroke mechanism.
Pathophysiological Mechanisms
The study proposes multifactorial IS mechanisms in PMN:
- Hypercoagulability: Nephrotic syndrome leads to urinary loss of anticoagulant proteins (e.g., antithrombin III) and elevated prothrombotic factors (fibrinogen, D-dimer).
- Atherogenesis: Severe dyslipidemia (LDL >160 mg/dL in 9/12) accelerates atherosclerosis, explaining LAA-related strokes.
- Cerebral small vessel disease (CSVD): Ubiquitous WMC and lacunar infarcts suggest chronic microvascular injury, potentially exacerbated by hypertension and immune complex deposition.
Clinical Implications and Future Directions
The high prevalence of CSVD and multi-territory infarcts in PMN patients underscores the need for aggressive management of traditional cardiovascular risk factors (hypertension, dyslipidemia) and thromboprophylaxis. However, the role of immunosuppression in reducing stroke risk remains unclear, as 4/12 patients developed IS while on steroids/immunosuppressants. Future studies should explore whether PLA2R antibody titers or specific immune pathways directly contribute to cerebrovascular injury.
In conclusion, ischemic stroke in anti-PLA2R-positive PMN is driven by a triad of hypercoagulability, accelerated atherosclerosis, and cerebral small vessel disease. Neuroimaging reveals a predilection for subcortical and multi-territory infarcts, with severe white matter changes indicating advanced microangiopathy. The poor renal and neurological outcomes observed highlight the necessity for integrated nephrological and neurological care in this high-risk population.
doi.org/10.1097/CM9.0000000000000610
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