Do we fully understand the risk factors associated with venous thromboembolism in nephrotic syndrome?

One of the most serious complications of nephrotic syndrome (NS) is thromboembolism, which includes both arterial and venous thromboembolic events. Arterial thromboembolism (ATE) in NS has been linked to traditional cardiovascular risk factors, whereas a number of factors have been associated with venous thromboembolic (VTE) events. A serum albumin level of <25 g/L bromocresol green (BCG) is one of the factors that has been associated with VTE. The Kidney Disease Improving Global Outcomes (KDIGO) glomerular nephritis guidelines 2021 use this albumin level as a cut-off for high thromboembolic risk and consideration of anticoagulation for VTE thromboprophylaxis.¹ A recent UK survey found that 93% of clinicians used serum albumin to determine need for VTE prophylaxis.² All clinicians would anticoagulate if the patient had albumin <20 g/L; however, when albumin was >25 g/L, only 46% would anticoagulate. 

This month, however, Liu and colleagues highlighted that the cut-off of albumin <25 g/L BCG did not cover almost 27% of VTE events in nephrotic patients across a 10-year review within their centre.³ In their study, membranous nephropathy (MN) still carried a significant risk of VTE when albumin was >25 g/L BCG, even when anti-PLAR2 levels were less likely to be positive. MN has been identified as an independent risk in many other studies, but, more recently, it has been postulated that anti-PLAR2 positivity may be associated with VTE risk. However, Liu’s study seems to suggest the VTE risk with MN may also be independent of anti-PLAR2 positivity. Another risk identified was lupus anticoagulant positivity, with three patients being diagnosed with antiphospholipid syndrome.

This study reminds us of the need for thorough consideration of all VTE risk factors when making decisions around anticoagulant thromboprophylaxis in nephrotic syndrome. Alongside albumin, other factors include primary disease and degree of proteinuria. As Liu et al highlight, primary diseases, such as systemic lupus erythematosus, may be associated with prothrombotic antiphospholipid antibodies, such as lupus anticoagulant. However, consideration of more traditional risks of VTE, such as age, immobility and obesity, are also important. Anticoagulation is not without its risks, and so risk stratification is key. The KDIGO guideline¹ points to a risk calculator developed specifically to determine benefit for VTE thromboprophylaxis for patients with MN, but it requires the clinician to input what risk ratio they deem suitable for bleeding and VTE.

Lui’s study highlights that we still have many uncertainties in patients with nephrotic syndrome, the first being what the risk factors are for VTE. Once fully elucidated, the next question is who would warrant anticoagulation and, if we are anticoagulating them, how long should we anticoagulate for? Liu et al found that over 20% of those who develop a VTE developed it six months after initial follow-up, as seen in other studies. In terms of anticoagulation, what should we be using and should this be at a therapeutic or prophylactic dose? 

The National Registry of Rare Kidney Diseases (RaDaR) and the National Unified Renal Translational Research Enterprise: Idiopathic Nephrotic Syndrome (NURTuRE-INS) study cohort are large databases recruiting and holding data on patients with these conditions, which may be the place to start in trying to answer some of these questions. 

A digest of the study can be ready here.

References

1. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group (2021) KDIGO 2021 Clinical practice guideline for the management of glomerular diseases. Kidney Int 100(Suppl 4): S1–276
2. Parker K, Choudhuri S, Lewis P et al (2023) UK prescribing practice of anticoagulants in patients with chronic kidney disease: a nephrology and haematology-based survey. BMC Nephrol 24: 9 
3. Liu YM, Gao S, Liu LJ (2024) The risk of thromboembolic events in patients with nephrotic syndrome and relatively high albumin levels: a study over 10 years. BMC Nephrol 25: 301
4. Lin R, McDonald G, Jolly T et al (2019) A systematic review of prophylactic anticoagulation in nephrotic syndrome. Kidney Int Rep 5: 435–47
5. Zhu H, Xu L, Liu X et al (2022) Anti-PLA2R antibodies measured by ELISA predict the risk of vein thrombosis in patients with primary membranous nephropathy. Ren Fail 44: 594­–600
6. Parker K, Ragy O, Hamilton P et al (2023) Thromboembolism in nephrotic syndrome: controversies and uncertainties. Res Pract Thromb Haemost 7: 102162