Epidemiologic data consistently show that adults with nephrotic syndrome are at substantially higher risk for both atherosclerotic and thromboembolic events than the general population [6]. The absolute burden of cardiovascular disease (CVD) in this group is strikingly high, even when adjusted for baseline comorbidities.

In a Danish nationwide cohort of nearly 4,000 adults with incident nephrotic syndrome, the cumulative incidence of arterial thromboembolic events (including myocardial infarction and stroke) reached 14.0% within 10 years, while VTE occurred in 7.7% of patients. Notably, the 1-year risk for these events was already elevated, 4.2% for arterial events and 2.8% for VTE, corresponding to hazard ratios of 3.1 and 7.1, respectively, compared to the general population [9].

These risks are not limited to secondary causes such as diabetes mellitus or lupus: in the United States cohort of biopsy-confirmed primary nephrotic syndrome, adjusted hazard ratios were also significantly elevated for acute coronary syndromes (2.6), heart failure (3.0), stroke (1.8), and VTE (2.6), with the highest event rates seen in patients with FSGS [2]. Importantly, cardiovascular events occurred early and often preceded progression to kidney failure, emphasizing their clinical relevance even in patients with preserved kidney function.

When compared with other chronic kidney disease (CKD) populations, patients with nephrotic syndrome appear to have a distinctly higher thrombotic and atherogenic profile, likely related to nephrotic syndrome-specific factors such as heavy proteinuria and hypoalbuminemia, which are not always present in non-nephrotic CKD. This elevated cardiovascular risk is driven by a unique combination of a variety of factors, including marked hyperlipidemia (often including elevated lipoprotein(a)), a hypercoagulable state with loss of antithrombin (AT) III, increased platelet aggregation, endothelial dysfunction, and fluid shifts. These features are rarely seen in proteinuria-free CKD and may not be adequately captured by standard CKD-based cardiovascular risk prediction models [5,10]. As a result, nephrotic patients may be under-classified in traditional risk categories, despite substantial actual risk.

The elevated cardiovascular risk in nephrotic syndrome arises from a complex interplay of traditional and disease-specific factors:

• Proteinuria: Heavy proteinuria itself is an independent marker of CVD risk. In large population studies, persistence of significant proteinuria portended a higher incidence of major CVD. For example, individuals with persistent proteinuria had a 1.8-fold higher risk of cardiovascular events than those with no proteinuria [11]. Reduction of proteinuria improves but does not eliminate risk [11].

• Dyslipidemia: Nephrotic syndrome induces a distinctive lipid profile including elevated low-density lipoprotein (LDL)-cholesterol, very low-density lipoprotein (VLDL), triglycerides, and lipoprotein(a) [12], together with impaired high-density lipoprotein (HDL) functionality. These qualitative and quantitative lipoprotein abnormalities are highly atherogenic and persist until proteinuria remits. Mechanistically, nephrotic syndrome upregulates proprotein convertase subtilisin/kexin type 9 (PCSK9) and downregulates lipoprotein lipase (LPL), leading to defective clearance of atherogenic particles and endothelial dysfunction [13].

• Hypertension: Hypertension is common in nephrotic syndrome (due to salt retention and renin angiotensin system [RAS] activation) and multiplies cardiovascular risk. Indeed, patients often have high baseline rates of hypertension. For example, SLE patients with nephritis had approximately 5-fold higher odds of hypertension than those without nephritis [14]. Even in primary nephrotic syndrome, uncontrolled blood pressure will worsen atherosclerotic risk and left ventricular dysfunction over time. Especially in nephrotic patients, stricter thresholds for proteinuria (e.g., <0.5–1.0 g/day) are often used as therapeutic targets. Although there is no specific guideline solely for nephrotic syndrome, observational studies show that intensive RAS blockade with the maximally tolerated dose of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) alone improves both renal and cardiovascular outcomes [15]. In line with this, the UKKA commentary on the KDIGO (Kidney Disease: Improving Global Outcomes) 2021 guidelines emphasizes that RAS blockade is indicated when proteinuria persists beyond 0.5 g/day [16].

• Hypoalbuminemia and hypercoagulability: Severe hypoalbuminemia (<2.5 g/dL) enhances coagulation by reducing circulating anticoagulants (e.g., AT III) and increasing platelet aggregation [17]. These alterations explain the high incidence of VTE, especially in MN, and may also contribute to arterial thrombosis [9].

These interrelated mechanisms underscore the need for early cardiovascular risk stratification and targeted intervention in all nephrotic syndrome patients (Fig. 1), not only to prevent progression of CKD but to mitigate the substantial burden of cardiovascular morbidity and mortality.

Nephrotic syndrome produces a characteristic dyslipidemia that strongly promotes atherosclerosis [18]. Patients develop hypercholesterolemia and hypertriglyceridemia, with elevations of VLDL and LDL and increases in apolipoprotein B-containing lipoproteins [13]. This results from a combination of increased hepatic lipoprotein synthesis (driven by hypoalbuminemia caused by excessive proteinuria) and impaired lipoprotein clearance [18,19]. In nephrotic syndrome, endothelial LPL and hepatic lipase activities are decreased and plasma levels of PCSK9 are elevated [13,18,20]. Elevated PCSK9 further reduces LDL‐receptor expression and raises LDL‐cholesterol. HDL particles are also abnormal in nephrotic syndrome, with an increase in immature HDL and impaired reverse cholesterol transport [18]. Notably, nephrotic syndrome patients often have dramatically elevated lipoprotein(a) levels [21], an atherogenic and thrombogenic lipoprotein. In addition, glomerular injury itself releases factors that connect nephrotic syndrome to lipid metabolism. For example, animal and human studies have identified angiopoietin-like 4 (ANGPTL4) as a podocyte-derived mediator. ANGPTL4 is upregulated in nephrotic syndrome and secreted into plasma, where it inhibits LPL activity and drives hypertriglyceridemia [19]. In experimental nephrotic syndrome models, circulating ANGPTL4 acts in a feedback loop: it reduces proteinuria via interaction with glomerular endothelium, but at the same time suppresses peripheral lipolysis, causing hypertriglyceridemia [19]. Suggesting that glomerular-derived ANGPTL4 links heavy proteinuria to the profound dyslipidemia of nephrotic syndrome [19,22]. Overall, the lipid abnormalities in nephrotic syndrome create an atherogenic profile that substantially raises the risk of coronary and cerebrovascular disease [18,21].

Nephrotic syndrome induces a hypercoagulable state that elevates both venous and arterial thrombotic risk. Multiple mechanisms are at play: urinary loss of natural anticoagulants (especially AT III, protein C, and protein S) and upregulation of procoagulant factors (fibrinogen, factor V and VIII, von Willebrand factor) create a prothrombotic balance [5,23]. Hypoalbuminemia and hemoconcentration increase blood viscosity, which causes platelets to become hyperaggregable. Clinically, nephrotic syndrome patients have very high rates of VTE (deep venous thrombosis, pulmonary embolism, renal vein thrombosis) [5]. Arterial thrombotic events (stroke, myocardial infarction) are also significantly increased: primary MN, for example, confers up to an eight-fold higher risk of arterial thromboembolism compared to the general population [23]. In one large cohort, the cumulative 6-month incidence of VTE was nearly 10% and arterial events approximately 5% [5].

The multifactorial nature of thrombotic risk in nephrotic syndrome aligns with Virchow’s triad:

• Venous stasis may result from peripheral edema compromising lower limb circulation, prolonged immobility (particularly during hospitalization), and aggressive diuretic use.

• Hypercoagulability is driven not only by hypoalbuminemia and urinary loss of anticoagulants but also by high-dose glucocorticoid therapy, which can enhance procoagulant activity.

• Endothelial injury may occur due to the insertion of central or peripheral venous catheters, which are frequently used in this patient population.

Evidence suggests that the magnitude of proteinuria and hypoalbuminemia correlate with venous thrombotic risk [5,24,25], whereas traditional atherosclerotic risk factors (hypertension, age, smoking, sex) predict arterial events in nephrotic syndrome [5]. Recent studies have refined the mechanisms: although AT deficiency has long been implicated, a 2023 multicohort study found that AT levels do not consistently explain the hypercoagulability of nephrotic syndrome [26]. Patients with and without severe AT loss showed similar thrombin-generation and thrombosis risk, indicating that AT III loss is not the sole driver [26]. Other factors are loss of heparin cofactors, increased clotting factor synthesis, and endothelial injury. In summary, nephrotic syndrome establishes a multifactorial prothrombotic milieu, characterized by elevated coagulation factors, reduced anticoagulant levels, and enhanced platelet activation, which significantly increases the risk of both venous and arterial thrombosis [5,23].

Nephrotic syndrome is characterized by systemic inflammation and endothelial dysfunction, both of which promote cardiovascular disease. Patients with nephrotic syndrome often exhibit elevated inflammatory markers (fibrinogen, interleukin-6, tumor necrosis factor alpha) even in the absence of overt infection [27]. These mediators, along with oxidative stress from lipid abnormalities, impair endothelial nitric oxide (NO) production. Indeed, nephrotic syndrome patients show markedly reduced flow-mediated dilation of the brachial artery [27]. In one study, nephrotic syndrome patients had significantly lower endothelium-dependent vasodilation than controls [27], and this dysfunction correlated inversely with free fatty acids and LDL levels [27].

Hypoalbuminemia increases the plasma free fatty acid/albumin ratio, leading to an increase in the delivery of free fatty acids to endothelial cells [27]. Elevated endothelial free fatty acids blunt NO synthesis and promote vasoconstriction and inflammation [28,29]. The same study found that nephrotic syndrome patients had higher insulin and glucose levels (indicating insulin resistance) [27], which further damages the endothelium and favors atherogenesis. Altogether, dyslipidemia and nonesterified fatty acids probably contribute to the increased risk of CVD seen in nephrotic syndrome [27]. Thus, a vicious cycle exists: proteinuria-driven dyslipidemia and insulin resistance induce endothelial injury, and the resulting vascular inflammation accelerates atherosclerosis in nephrotic syndrome.

Heavy proteinuria and hypoalbuminemia in nephrotic syndrome affect intravascular volume and neurohormonal regulation. The classic “underfill hypothesis” states that plasma oncotic pressure falls (due to albumin loss), causing fluid shift into the interstitium and relative intravascular hypovolemia [30]. This volume contraction activates the RAS, sympathetic nervous system, and vasopressin, driving renal sodium and water retention [30]. The resulting hypervolemia produces hypertension, increased cardiac output, and left ventricular strain. Angiotensin II and aldosterone themselves have harmful vascular effects (proliferation, oxidative stress, fibrosis) that further increase CVD risk. On the other hand, some evidence (“overfill” mechanisms) shows that intrarenal factors (e.g., filtered serine proteases) directly stimulate renal sodium reabsorption via epithelial sodium channels in the distal tubule [30]. Either way, nephrotic syndrome is often accompanied by salt retention and hypertension. This neurohormonal activation amplifies cardiovascular risk by raising blood pressure and promoting vascular remodeling. Importantly, blockade of RAS with ACE inhibitors or ARBs not only reduces proteinuria but also mitigates hypertension and cardiovascular stress in nephrotic syndrome patients.

Beyond systemic effects, intrinsic glomerular factors in nephrotic syndrome can directly influence cardiovascular pathology. For example, podocyte injury changes the glomerular basement membrane charge and heparan sulfate, which may release circulating endothelial toxins. Nephrotic syndrome is associated with elevated circulating mediators like vascular endothelial growth factor, endothelin, and oxidized lipids, which promote endothelial dysfunction. The ANGPTL4 story illustrates this crosstalk: podocytes in nephrotic syndrome overproduce a hyposialylated form of ANGPTL4 that increases proteinuria [31], whereas systemic ANGPTL4 reduces proteinuria but inhibits peripheral LPL, causing hypertriglyceridemia [19]. In effect, the diseased glomerulus “signals” to the vasculature and liver, linking kidney injury with atherogenic dyslipidemia. Finally, genetic or secondary glomerular diseases can compound risk: for instance, nephrotic syndrome due to FSGS or diabetic kidney disease often coexists with metabolic syndrome traits. CKD itself (often present in adult nephrotic syndrome) induces a pro-inflammatory, prooxidant state. All these glomerular-specific and CKD-related factors, together with the hemodynamic and metabolic changes above, create a “perfect storm” for accelerated cardiovascular disease in nephrotic patients.

Several clinical risk prediction models are available to estimate cardiovascular risk, but most are not specifically tailored to patients with nephrotic syndrome. Common tools such as the Framingham Risk Score, Atherosclerotic Cardiovascular Disease (ASCVD) Pooled Cohort Equations, and the European Systematic Coronary Risk Evaluation (SCORE) system estimate 10-year cardiovascular risk based on traditional factors (age, cholesterol, blood pressure, smoking, diabetes melliuts), but they do not incorporate kidney-specific parameters like proteinuria or hypoalbuminemia. The QRISK3 model includes CKD stages 3 to 5, offering slightly more relevance, yet it still lacks nephrotic syndrome-specific characteristics. Recent CKD-focused models, such as those derived from the CRIC study [32], have demonstrated improved predictive accuracy by integrating kidney function and biomarkers. However, no validated risk calculators currently exist for nephrotic syndrome specifically. Therefore, while standard tools can provide a general estimate, they may significantly underestimate true cardiovascular risk in nephrotic syndrome patients. Clinical judgment, along with supplemental use of biomarkers and imaging, remains essential for individualized risk stratification in this population.

Nephrotic syndrome is associated with marked hyperlipidemia. In the SHARP trial of non-dialysis CKD patients, including many with heavy proteinuria, simvastatin plus ezetimibe reduced major atherosclerotic events by 17% over 4.9 years, with a mean LDL-cholesterol reduction of about 32 mg/dL [34]. Based on these and other data, lipid-lowering therapy with statins is generally recommended for most patients with CKD, particularly those aged ≥50 years (KDIGO 2024: 1A recommendation if estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m²; 1B if eGFR ≥60 mL/min/1.73 m²) [35,36]. The KDIGO 2021 glomerular disease guideline also supports statin use in adults with persistent proteinuria and/or additional risk factors [16]. However, in young patients with nephrotic syndrome and no established cardiovascular risk factors, especially when a short disease course with expected remission is likely, there is currently limited evidence supporting routine statin therapy. Thus, the decision to initiate statins in this population should be individualized, weighing the expected duration of nephrotic syndrome and baseline cardiovascular risk. Practical clinical thresholds that may guide this decision include LDL-C >190 mg/dL, persistent nephrotic-range proteinuria (>3 months), a strong family history of premature cardiovascular disease, or the presence of additional CKD-related risk factors such as hypertension or smoking [37,38].

Although statin therapy has not yet been clearly proven to reduce major adverse cardiovascular events in randomized trials of nephrotic syndrome specifically [39], retrospective data suggest a possible benefit in reducing VTE [39]. Moreover, ezetimibe in combination with statins, as shown in SHARP, can further lower LDL and may be considered in patients not reaching lipid goals or with statin intolerance [34]. Given the lack of validated cardiovascular risk calculators specific to nephrotic syndrome, a practical approach is to use general population risk prediction tools (e.g., ASCVD or SCORE) with caution and clinical judgment. The 2024 KDIGO CKD guideline recommends considering a lower threshold for intervention [35], such as a 10-year cardiovascular risk ≥7.5% instead of 10%, particularly in younger patients with CKD who may be at underestimated risk due to factors not captured in standard models (e.g., proteinuria, hypoalbuminemia). Overall, statin therapy is recommended for nearly all patients with nephrotic syndrome aged >50 years and/or with eGFR <60 mL/min/1.73 m², in line with KDIGO 2024 (grade 1A and 1B recommendations). In contrast, for younger patients with preserved kidney function and a likely short disease duration, such as steroid-sensitive MCD, the decision should be individualized. The limited evidence in this group makes it reasonable to defer statin therapy unless additional cardiovascular risk factors are present [32]. These findings suggest that while the primary cardiovascular benefit of statins in nephrotic syndrome is suspected, it has not yet been clearly demonstrated by randomized studies. Nevertheless, statins are frequently used, especially in cases with very high cholesterol levels, since the expected risk reduction and overall safety profile of statins are generally considered to be positive [40].

According to the updated 2024 KDIGO guidelines for CKD, a target systolic blood pressure of <120 mmHg is still recommended following standardized office measurement, provided it is well tolerated [35]. However, it should be noted that blood pressure targets vary between major guidelines: the European Society of Cardiology typically recommends a systolic target of 130–139 mmHg, while the American Heart Association suggests a stricter goal of <130 mmHg in high-risk patients [41,42]. These differences reflect varying interpretations of available evidence and underline the need for individualized treatment decisions based on comorbidities, age, and tolerance. This recommendation is supported by evidence showing that intensive blood pressure control can slow CKD progression and reduce cardiovascular risk. While this represents a continuation of the shift away from earlier targets such as <130/80 mmHg, the guidelines emphasize the importance of individualization [35]. In clinical practice, a systolic blood pressure target of ≤130 mmHg is generally pursued for patients with nephrotic syndrome. This more moderate target reflects the need to balance efficacy with safety, especially in older adults or patients with frailty or increased risk of adverse effects from intensive blood pressure lowering. Therefore, although <120 mmHg remains the ideal target, particularly in younger and high-risk patients, clinicians are advised to tailor treatment goals based on patient-specific factors such as age, comorbidities, and tolerance [35].

In cases of albuminuria/proteinuria, ACE inhibitors or ARBs are the first-line treatment. These medications lower blood pressure and, through blockade of the RAS, reduce the progression of kidney damage in a proteinuria-dependent manner. Meta-analyses show that ACE inhibitors reduce the combined risk of cardiovascular death, myocardial infarction, and stroke by approximately 15% in high-risk patients without heart failure [43]. ARBs show a slightly lower effect (approximately 7% risk reduction) but are valuable alternatives, for example, in cases of ACE inhibitor intolerance. The combination of both drug classes is not recommended due to an increased rate of side effects (such as hyperkalemia and deterioration of kidney function) [43]. Especially in nephrotic patients, stricter thresholds for proteinuria (e.g., <0.5–1.0 g/day) are often used as therapeutic targets. Although there is no specific guideline solely for nephrotic syndrome, studies in diseases such as immunoglobulin A nephropathy (e.g., the STOP-IgAN trial) show that intensive RAS blockade with the maximally tolerated dose of ACE inhibitors or ARBs alone improves renal outcomes [15].

Nephrotic syndrome is associated with a hypercoagulable state: losses of AT III, increased thrombopoiesis, altered fibrinolytic factors, and elevated platelet activity lead to a significantly increased risk of both venous and arterial thromboses. Studies show that patients with nephrotic syndrome can have a VTE risk of up to 10%–40% within the first few months after diagnosis, depending on serum albumin levels, underlying etiology (particularly MN [44]), and other comorbidities [6,45]. Due to the high risk of thrombosis, prophylactic anticoagulation is considered for selected patients with nephrotic syndrome. A commonly cited threshold is a serum albumin level of <2.0–2.5 g/dL, depending on the method of albumin measurement. It is important to recognize that different laboratory methods for albumin measurement, such as bromcresol green (BCG), bromcresol purple dye-binding assays, or various immunoassays, systematically result in different albumin values, which can substantially impact clinical decision-making [46]. Markov simulation models suggest initiating thrombosis prophylaxis when albumin levels fall below 2.5 g/dL [45,47,48]. The rationale is that VTE rates increase drastically when albumin levels are very low. In cases of confirmed MN with nephrotic syndrome, the KDIGO 2021 guidelines suggest assessing VTE risk on an individual basis and considering anticoagulation in high-risk patients [49]. The bleeding risk is carefully weighed in this context, for example, using the HAS-BLED (hypertension, abnormal kidney/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, and drugs/alcohol concomitantly) score. Oral anticoagulation with vitamin K antagonists is considered the standard for VTE prophylaxis, with an international normalized ratio target between 2.0 and 3.0 to effectively prevent thrombosis [50]. As an alternative, the updated KDIGO recommendations propose a regimen of low-molecular-weight heparin combined with low-dose aspirin [49,51]. This combination targets both venous and arterial thromboses (with aspirin addressing arterial events), although the evidence for the latter remains limited. It is important to consider the individual patient history: in patients with known risk factors (such as prior thrombosis, malignancy, or immobility), prophylactic treatment should be more strongly considered.

New evidence from Gholizadeh et al. [52] suggests that for patients with serum albumin between 2.0 and 3.0 g/dL, aspirin monotherapy may be a reasonable prophylactic option, depending on the patient’s individual thrombotic and bleeding risk profile. Their proposed clinical algorithm supports tailored approaches based on albumin thresholds and risk stratification, advocating for aspirin alone in patients with moderate hypoalbuminemia and either low thrombotic or high bleeding risk [52].

The key factor is the risk-benefit assessment: according to modeling studies, prophylactic anticoagulation significantly reduces the risk of VTE but can cause bleeding. Therefore, it is recommended to use anticoagulation when serum albumin is <2.5 g/dL, when the BCG assay is used, and additional risk factors are present (e.g., MN, high thromboembolism nomogram score, immobility) [45,49]. In cases of moderate hypoalbuminemia or elevated bleeding risk, close clinical monitoring is often preferred, and low-dose aspirin may be used as an alternative. While current recommendations are largely based on observational data and simulation models, large RCTs are unlikely: Rankin et al. [53] estimated that to demonstrate a statistically significant benefit of anticoagulation over no prophylaxis in primary nephrotic syndrome, a trial would need nearly 972 participants to achieve 80% power, an unfeasible number given the rarity of the condition. Preliminary observational data from nephrotic syndrome patients treated with direct oral anticoagulants (DOACs) have shown acceptable safety outcomes: in a Danish series of 21 patients, thromboembolic events were limited and bleeding was rare [54] and a multicenter retrospective comparison found lower rates of major bleeding with DOACs compared with warfarin [55].

Thus, recent expert reviews continue to describe this as a “clinical dilemma,” necessitating reliance on individualized risk stratification in the absence of large RCT evidence (Table 2).