Risk Factors for Stroke in Patients with Nephrotic Syndrome: Experience from Two Centers in Poland

Introduction

Nephrotic syndrome (NS), which present with clinical features such as heavy proteinuria, edema, and hyperlipidemia, is associated with a widely known increased risk of developing thromboembolic events (TEs). Although multifactorial, thrombogenesis in the setting of NS is hypothesized to be mainly due to a hemostatic shift into a hypercoagulable state. With the nephrotic-range proteinuria many important anti-coagulatory proteins (antithrombin and protein S) with a similar molecular size of albumin are excreted into the urine, leading to a compensatory hepatic synthesis of lipids and pro-thrombotic proteins (fibrinogen, factor V and VII) [1]. Depending on the underlying glomerulopathy and degree of diagnostic evaluation, the reported incidence of venous thromboembolic events (VTEs) in patients with NS can vary between 2% to 37% [2]. The association between arterial thromboembolic events (ATEs) and NS on the other hand has been questionable in the past, however, newly aggregated data clearly suggest an increased risk of ATEs in patients with NS [3], in particular a 1.8-fold increased risk of acute ischemic stroke (aIS) [4]. In comparison, same study reports a 2.6-fold increased risk of VTEs.

Histopathological diagnosis of membranous nephropathy (MN), higher proteinuria and lower serum albumin levels increase the risk of VTEs in patients with NS [5-9]. Such findings have however not been replicated in studies analysing risk factors for ATEs [8, 9], indicating differences in pathophysiologic mechanisms between VTEs and ATEs in this population. Although data is limited, risk of developing ATEs among patients with NS seems to be rather connected to classic atherosclerotic risk factors such as older age, hypertension, diabetes mellitus, prior ATEs, smoking and impaired renal function [8, 9]. Furthermore, a limitation to these studies is the inclusion of all types of ATEs and not performing subgroup analyses for the different sites of ischemia. Most of the time patients with stroke unfortunately face a poor prognosis [10, 11], and investigating possible predisposing factors could provide preventive and predictive measures for clinicians. Moreover, information of such kind could also give further insight on the pathogenesis of NS-associated ATEs. Due to its rarity, the data on cerebrovascular disease in patients with NS is sparse and to the best of our knowledge, a study examining risk factors for the outcome of aIS and intracerebral hemorrhage (ICH) in patients with NS is missing. Therefore, the goal of this study was to identify risk factors for the development of stroke among patients with NS.

 

Methods

Data extraction

Between January 1st 2010 and December 31st 2021, 2303 hospitalized patients with NS-related diagnoses (ICD-10: N04.x, N06.x, N08.x) were identified at two hospitals in Poland. Of these, 56 patients also had a diagnostic code for aIS or ICH (ICD-10: I60.x-I63.x). Medical charts of patients with NS and stroke were thereafter precisely reviewed to confirm NS based on available laboratory and clinical data [12]. We also excluded those with stroke prior to the first reported episode of NS, which resulted in a final inclusion of 18 patients (14 with aIS and 4 with ICH). A control group was additionally obtained, consisting of 27 randomly picked patients hospitalized during the same study period, who were diagnosed for NS but no stroke following their first reported episode of NS.

Available baseline laboratory values, results from urinalysis, comorbidities, pharmacological treatment, and other clinical data which was considered relevant was collected for all patients included in the study. Additionally, we also obtained data on the clinical presentation of aIS and ICH for those with NS who developed it during follow-up. Based on information from medical charts, those with aIS also had their etiology classified according to the TOAST system. The TOAST classification system denotes 5 main subtypes of aIS, those being 1) large artery atherosclerosis, 2) cardioembolism, 3) small-vessel occlusion, 4) stroke of other determined etiology (e.g., vasculitis, non-inflammatory vasculopathies, microangiopathy, hypercoagulable state) or 5) stroke of undetermined etiology. Estimated glomerular filtration rate (eGFR) was calculated using the 2009 CKD EPI Creatinine formula. Ethical approval was granted from the local Ethics Committee (NKBBN/1007/2021-2022). Stroke in this cohort was defined as aIS or ICH.

Statistical analysis

All extracted variables were examined as potential risk factors. Risk factors for stroke were evaluated using an unadjusted Cox regression yielding a hazard ratio (HR) with a 95% confidence interval (CI), with the underlying time scale being time from first reported episode of NS to date of stroke or last follow-up. Continuous variables are presented as mean (SD) and categorical data as frequencies (%). For continuous data, differences were evaluated by the Student’s t-test. Categorical variables were compared with chi square test or Fisher’s exact test. If ≤ 20% of expected cell counts were less than 5, then the chi-square test was used, and if > 20% of expected cell counts were less than 5, then Fisher’s exact test was applied. A p-value < 0.05 was considered as statistically significant. All statistical analyses were performed using IBM SPSS Statistics version 29 (IBM Corp.).

In addition to our two-centre experience, a meta-analysis was carried out on all 3 studies within the litterature (including ours) analysing factors associated with an increased risk of ATEs in patients with NS. For the meta-analysis, all extractable dichotomous variables (reported in at least 2 studies) associated with ATEs among patients with NS, examined through a cox regression with a hazard ratio (HR) and 95% confidence interval (CI), were pooled into generic inverse variance forest plots. Random-effects models were used and the heterogeneity of the overall HR was calculated using the I² statistic. Publication bias was assessed by visual inspection of funnel plot asymmetry. P < 0.05 was considered statistically significant. All analyses were performed using Review Manager version 5.4 (Cochrane IMS).

 

Results

A total of 45 patients with NS were included with a mean follow-up of 6 years. Of those included in the cohort, 14 (31.1%) were diagnosed with aIS and 4 (8.9%) with ICH during follow-up. The most common type of aIS was large artery atherosclerosis (50%) followed by stroke of undetermined (21.4%) or other determined etiology (21.4%). The most common locations of ICH were the cerebral hemispheres (50%) and brainstem (25%). Relapse of NS at the onset of stroke occurred in 7 (50%) and 1 (25%) of patients with aIS and ICH, respectively. Of those who developed stroke, 5 (27.7%) suffered a stroke within the 1^st year of first NS episode, 6 (33.3%) within 1-3 first years of first NS episode, and 7 (38.9%) >3 years after their first reported episode of NS.

	NS with stroke	NS without stroke	P-value
Number of patients	18	27	–
Mean (SD) age, years	53.6 (22.1)	47.1 (16.5)	0,268
Male sex	9 (50.0%)	18 (66.7%)	0,264
Proteinuria (g/day)*	4.81 (1.60)	8.46 (7.49)	0,218
Serum creatinine (mg/dL)*	2.63 (1.69)	1.95 (1.29)	0,294
Mean (SD) eGFR mL/min/1.73m2*	37.3 (24.6)	54.5 (48.2)	0,143
Etiology for NS			<0,001
Minimal change disease	0 (0.0%)	2 (8.0%)
Amyloidosis	0 (0.0%)	2 (8.0%)
Diabetic nephropathy	8 (44.4%)	2 (8.0%)
Lupus nephritis	4 (22.2%)	0 (0.0%)
Focal segmental glomerulosclerosis	0 (0.0%)	5 (20.0%)
Multiple myeloma	0 (0.0%)	1 (4.0%)
Other or unspecified	6 (33.3%)	13 (52.0%)
Hypertension	16 (88.9%)	10 (38.5%)	<0,001
Diabetes	11 (61.1%)	4 (15.4%)	0,002
Smoker	4 (26.6%)	2 (7.7%)	0,168
Other cardiovascular disease(s)	7 (38.9%)	2 (7.7%)	0,021
Prior ATEs	9 (52.9%)	0 (0.0%)	<0,001
Prior VTEs	1 (5.9%)	2 (7.7%)	1
Thrombocytes 10^9 (L)*	236 (120.3)	310 (72.9)	0,069
Erythrocytes 10^9 (L)*	4.22 (1.36)	4.72 (0.79)	0,253
Hematocrit (%)*	33.9 (8.00)	40.2 (5.77)	0,036
Hemoglobin (g/dL)*	11.6 (2.97)	14.1 (2.31)	0,029
Uncorrected calcium (mg/dL)*	7.00 (2.93)	7.93 (0.51)	0,548
Sodium (mmol/L)*	127 (31.4)	139 (3.37)	0,185
Potassium (mmol/L)*	5.05 (1.55)	4.20 (0.57)	0,068

Table 1. General demographics and characteristics at baseline.
NS: Nephrotic syndrome; ATEs: Arterial thromboembolic events; VTEs: Venous thromboembolic events; eGFR: Estimated glomerular filtration rate. *More than 10% missing data.

At baseline, patients with NS that developed stroke (aIS or ICH) were more commonly diagnosed with diabetic nephropathy (44.4% vs 8.0%, p-value < 0.001), lupus nephritis (22.2% vs 0%, p-value < 0.001),  hypertension (88.9% vs 38.5%, p-value < 0.001), diabetes mellitus (61.1% vs 15.4%, p-value = 0.002), other cardiovascular disease (e.g ischemic heart disease, peripheral artery disease,) 38.9% vs 7.7%, p-value =0.021), and more often had prior episodes of ATEs (52.9% vs 0.0%, p-value < 0.001) (Table 1). Patients with NS that developed stroke during follow-up also had lower levels of hemoglobin (p-value = 0.029) and hematocrit (p-value = 0.036) (Table 1) at baseline. Further baseline demographics and characteristics can be found in Table 1.

	NS with stroke (n = 18)	NS without stroke (n = 27)	P-value
Heparin	1 (6.7%)	0 (0.0%)	0,357
LMWH	10 (62.5%)	11 (42.3%)	0,204
Warfarin	1 (6.3%)	0 (0.0%)	0,372
NOAC	1 (6.3%)	0 (0.0%)	0,381
Immunosuppressive agents	5 (31.3%)	19 (70.4%)	0,013
Acetylsalicyl Acid/Clopidogrel	10 (62.5%)	6 (22.2%)	0,008
Statins	12 (80.0%)	14 (51.9%)	0,072
Beta-blockers	14 (82.4%)	9 (36.0%)	0,003
Calcium channel blockers	7 (43.8%)	4 (15.4%)	0,07
RAASi	9 (56.3%)	12 (44.4%)	0,454
Diuretics	13 (86.7%)	23 (85.2%)	1.0

Table 2. Pharmacological treatment during follow-up (before the onset of stroke). NS: Nephrotic syndrome; LMWH: Low-molecular weight heparin; NOAC: Novel oral anticoagulant drugs; RAASi: Renin angiotensin aldosteorne system inhibitors.

Patients with NS that developed stroke during follow-up were less commonly prescribed with glucocorticosteroids (27.3% vs 71.4%, p-value = 0.028) but not with other immunosuppressants (0.0% vs 6.6%, p-value =1.0) or low-molecular weight heparin (LMWH) (62.5% vs 42.3%, p-value = 0.204) (Table 2) at baseline. Moreover, during follow-up up until stroke, these patients were also more commonly prescribed with beta-blockers (82.4% vs 36.0%, p-value = 0.003) and acetylsalicylic acid/clopidogrel (62.5% vs 22.2%, p-value = 0.008) (Table 2). No significant differences for medication prescription were detected between patients with aIS and ICH.

	HR (95%CI)	P-value
Hypertension	3.00 (0.68-13.3)	0,148
Diabetes mellitus	2.85 (1.10-7.39)	0,03
Smoker	8.29 (2.20-31.2)	0,002
Prior ATEs	2.86 (1.09-7.53)	0,03
Prior VTEs	0.41 (0.05-3.35)	0,409
Age > 55 years	4.84 (1.48-15.8)	0,009
eGFR < 60 ml/min/1.73m2	2.15 (0.43-10.7)	0,351

Table 3. Risk factors for stroke in patients with nephrotic syndrome. ATEs: Arterial thromboembolic events; VTEs: Venous thromboembolic events; eGFR: Estimated glomerular filtration rate.

In univariate analysis, statistically significant risk factors for stroke in patients with NS were diabetes mellitus (HR 2.85, 95% CI 1.10-7.39; p-value = 0.03), diabetic nephropathy (HR 2.74, 95% CI 1.06-7.07; p-value = 0.038) smoking status (HR 8.29, 95% CI 2.20-31.2; p-value = 0.002), prior ATEs (HR 2.86, 95% CI 1.09-7.53; p-value = 0.03) and age > 55 years old (HR 4.84, 95% CI 1.48-15.8; p-value = 0.009) (Table 3). Hypertension (HR 3.00, 95% CI 0.68-13.3; p-value = 0.148) eGFR < 60 (HR 2.15, 95% CI 0.43-10.7; p-value = 0.351) lupus nephritis (HR 2.27, 95% CI 0.73-7.13; p-value = 0.159), male sex (HR 0.77, 95% CI 0.30-1.96; p-value = 0.586), prior episodes of VTEs (HR 0.41, 95% CI 0.05-3.35; p-value = 0.409), administration of LMWH (HR 0.88, 95% CI 0.22-3.43; p-value = 0.848) or glucocorticosteroids at baseline (HR 0.33, 95% CI 0.07-1.59; p-value = 0.169), were not associated with an increased risk of stroke.

In the meta-analysis, a total of 1091 patients were included, of which 119 (10.9%) developed an ATE at follow-up. In univariate analysis, statistically significant risk factors for ATEs among patients with NS were prior ATEs (HR 4.45, 95%CI 1.52-13.1; p-value = 0.007), hypertension (HR 2.06, 95%CI 1.40-3.04; p-value = 0.0003), diabetes (HR 2.70, 95%CI 1.28-5.68; p-value = 0.009), smoking (HR 2.78, 95%CI 1.35-5.73; p-value = 0.005), while male sex (HR 1.32, 95%CI 0.80-2.16; p-value = 0.27) and prior VTEs (HR 1.50, 95%CI 0.12-18.4; p-value = 0.75) were not (Figure 1A-F).

 

Discussion

Despite the frequent and well-known entity of TEs among patients with NS, the fully to be unravelled pathophysiology and unclear data on risk factors limits risk-stratification and prevention in clinical setting. Mahmoodi et al. in a retrospective study of almost 300 patients with NS, demonstrated male sex, diabetes mellitus, hypertension, smoking, prior ATEs, older age and reduced kidney function to be risk factors for ATEs [8]. In an even bigger cohort of almost 800 patients with MN, classic atherosclerosis risk factors such as older age, smoking, hypertension and prior ATEs were also found to be associated with the development of ATEs [9]. This is mostly in accordance with our study where we found diabetes mellitus, smoking, prior ATEs and age > 55 as risk factors for stroke in the context of NS. While we did not find hypertension to be a statistically significant risk factor, this comorbidity was more common among those with stroke as compared to those without (88.9% vs 38.5%). Moreover, in our study there were not patients with MN. However, we believe this conflicting information to be due to our low sample size and insufficient statistical power. A relationship between severity of proteinuria and/or hypoalbuminemia and VTEs is much more established [2, 5-9], while for ATEs the evidence is lacking. As we had a moderate amount of missing data on serum albumin and proteinuria levels, we could not properly evaluate those parameters as risk factors. Still, we found proteinuria levels at baseline to be somewhat comparable between those with and without stroke, which does not suggest a higher thromboembolic risk in our cohort. Yet the SD was relatively wide, and its interpretation should be cautious. Mahmoodi et al. found no apparent increase in risk for ATEs among those with lower serum albumin levels, higher proteinuria, or higher proteinuria/albumin ratio. Zou et al. in their previously mentioned cohort of nearly 800 patients with MN, found in univariate analysis proteinuria > 8.5 g/L to be a risk factor for ATEs [9], but this association was no longer statistically significant in multivariate analysis (p-value 0.11). Another interesting finding by Zou et al. was lower serum albumin levels among those that developed ATEs within the first 6 months of MN diagnosis, compared to those that developed ATEs after 6 months [9]. This supports the hypothesis of two different pathophysiological mechanisms of ATEs in the setting of NS. ATEs with an early onset (within the first 6 months) are usually connected to hypercoagulability, while those with delayed onset (after the first 6 months) are related to the chronic progression of atherosclerotic plaques. However, it cannot be disregarded that the sudden active nephrotic-range proteinuria could still play a role in the pathophysiology of all ATEs, regardless of onset. Numerous case reports have reported the onset of ATEs together with active nephrotic-range proteinuria [13-17]. Similarly, in our cohort 50% of patients had a relapse of NS at the time of aIS. Apart from the classic cardiovascular risk factors, this indicates that nephrotic-range proteinuria, hypoalbuminemia, and hypercoagulability could also be involved in the development of ATEs with a delayed onset.

In our cohort, NS subjects with stroke as compared to those without seemed to have lower (even though non-significant) sodium levels at baseline. Moreover, while diuretic use at baseline was unavailable, diuretic use at follow-up was comparable. Therefore, combining this information, it can be speculated that those that developed stroke were at fluid overload when hospitalized for their first NS episode. This could’ve contributed to a higher risk of stroke due to increased blood pressure, however this is unlikely to be the case in our population as many strokes occurred years after initial NS diagnosis. Hemoglobin levels were statistically significantly lower among those with NS who developed stroke at follow-up. This might have contributed to the multifactorial pathogenesis of stroke, as even anemia may increase the risk of aIS in population-based studies [18, 19]. It is hard to determine why hemoglobin levels had such a significant difference between the two groups, however it can be speculated. However, based on our data such a question cannot be fully answered. Furthermore, the lower hemoglobin together with increased potassium levels and more prevalent use of antiplatelet drugs during follow-up among those NS patients who developed stroke, might hint towards higher rates of gastrointestinal bleeding.

Data aggregated over the last decade strongly suggests MN to be associated with an increased risk of VTEs [2], yet its association is less certain in the context of ATEs. Our study demonstrated diabetic nephropathy in the setting of NS to be a risk factors for stroke, confirming how classic cardiovascular heavily influence the risk of developing stroke in the studied population. No subjects in our cohort had definite histopathological findings of MN, and as such we could not evaluate its association with the risk of stroke. Moreover, Mahmoodi and his colleagues found those diagnosed with diabetic nephropathy to have the highest annual incidence (7.4%) of ATEs, while this number for those with MN was at 1.3% [8]. Retrospective data collection has its limitations with regards to selection bias and adequate sample size. However, a recently published study by Alan et al. assembled a cohort of 907 adults diagnosed with primary NS using population-based data, which revealed patients with MN be at an over 2-fold increased risk of developing aIS [20]. Same report demonstrated a 3.2-fold risk increase for acute coronary syndrome among those with focal segmental glomerulosclerosis (FSGS), but non-significant association with aIS.  NS patients with stroke in our cohort more commonly had lupus nephritis, yet this was not a statistically significant risk factor, even though it was leaning towards statistical significance (p-value = 0.159). In fact, those with systemic lupus erythematous are at an increased risk of aIS, ICH and other ATEs [21]. Another study which consisted of patients hospitalized for NS, found lupus nephritis to be a risk factor for VTEs during hospitalization [22]. However, the 2 studies analysing risk factors for ATEs in NS did not include patients with lupus nephritis [8, 9], and thus its predisposition to ATEs in the setting of NS remains unclear. Risk-estimates for developing VTEs according to other types of glomerulonephritis have also been examined. A Canadian registry-based study found both MN and FSGS, as compared to IgA nephropathy, to increase the risk of developing VTEs [23]. Yet other data suggests incidence of renal vein thromboses in adult NS to be comparable to other types of glomerulonephritis (apart from MN) [1]. Much less data exists on the type of glomerular disease and risk of developing ATEs, highlighting our novel findings of diabetic nephropathy and possibly lupus nephritis being high-risk groups.

Concerns have been raised whether use of glucocorticosteroids could increase the risk of TEs in patients with NS. Intravenous administration of glucocorticosteroids in patients hospitalized for NS showed higher risk-estimates for developing VTEs [22]. Another report found a higher incidence of VTE in patients with MN receiving glucocorticosteroids [24]. To the best of our knowledge, we are the first to explore such an association in the context of ATEs, where we found no apparent risk increase for stroke among NS glucocorticosteroid users, as compared to non-glucocorticosteroid users.

Guidelines on the prevention of thromboembolism in the context of NS remain uncertain [25]. While a prophylactic anticoagulation algorithm that takes into account serum albumin levels, bleeding risk and histopathological findings has been developed to aid clinical decision on which NS patients would benefit from thromboembolic prophylaxis [26], it is based on limited data available in the literature. A recent meta-analysis suggests that prophylactic anticoagulation in patients with primary NS could decrease the risk of thromboembolic events without any serious bleeding risk [27]. However, as the outcome in most of the studies exploring anticoagulation therapy is all types of thromboembolism or VTEs [27], analyses on prophylactic anticoagulation for the prevention of specifically ATEs in NS are lacking. Considering that ATEs in NS seem to be related to classic cardiovascular risk factors, one could state the pharmacological approach should be the same as in standard high-risk cardiovascular patients. According to the “Kidney Disease: Improving Global Outcomes” guidelines, warfarin is recommended as the first-line prophylactic anticoagulant in NS [25]. Yet LMWH remains more commonly used in clinical practice [27], including from our bicentric experience. Interestingly, our study additionally found that administration of LMWH in patients admitted for NS did not affect the risk-estimates for developing stroke, which might question its efficacy in this subpopulation. It is however important to mention that this finding is limited due to lack of information on dosages and indication. Yet, another study replicated similar findings to ours, where use of prophylactic LMWH showed no significant decrease in incident ATEs among patients with MN [28]. By investigating anti-factor-Xa activity after administration of enoxaparin, Matyjek et al. found enoxaparin to have a decreased efficacy in severe NS, as compared to non-proteinuria controls [29]. The decreased effectiveness of LMWH among patients with NS could be attributed to the urinary loss of the heparin ligand antithrombin III [29, 30]. Other suggested mechanisms impairing the efficacy of LMWH in NS are an increased renal clearance of LMWH and decreased drug absorption from the subcutaneous tissue secondary to edema [29]. As such, it sheds light on whether it would be necessary to adjust the dosage of LMWH based on the severity of proteinuria in patients with NS. Future studies are necessary to establish optimal dose of LMWH for the prevention of thromboembolism without concomitant bleeding risk in the setting of NS. As a whole, data on prophylactic anticoagulation in the setting of NS is lacking, as even newer anticoagulation drugs such as factor Xa inhibitors and direct thrombin inhibitors have not been systematically studied in this subpopulation.

 

Limitations of the study

There are several limitations to be addressed. Although novel, the findings of this study are limited owing to its small sample size and retrospective design. Moreover, despite data collection at two different institutions, the number of NS patients with cerebrovascular disease was low and therefore we could not analyze the risk factors for aIS and ICH separately. Moreover, with the low sample size we did not perform a multivariate analysis owing to overfitting of the model. Missing data on baseline laboratory values and lacking information on histopathological results in a minority of patients are of greatest concern in terms of bias. As such, we could not properly evaluate the risk-estimates for developing stroke in NS depending on serum albumin levels, degree of proteinuria and histopathological diagnosis.

 

Conclusion

Although incidence of stroke in patients with NS is low, it most commonly occurs within the first 3 years of diagnosis. In this study we found older age, diabetes mellitus, prior ATEs and smoking status to increase the risk of developing stroke in patients with NS, while LMWH had no apparent protective effects. Further studies with larger study populations exploring the factors associated with the development of ATEs in the setting of NS are warranted.

 

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