Hypercoagulability in nephrotic syndrome

INTRODUCTION — Patients with the nephrotic syndrome (proteinuria greater than 3.5 g/day and hypoalbuminemia [less than 3 g/dL]) are at increased risk for venous thrombosis, particularly deep vein thrombosis (DVT) and renal vein thrombosis (RVT) [1-4]. Pulmonary embolization (mostly asymptomatic) is relatively common, and there are case reports of cerebral venous thrombosis [1-4]. Arterial thromboses (eg, limb and cerebral) also occur with higher frequency than in the general population [4-7].

This topic will review the epidemiology and pathogenesis of hypercoagulability in the nephrotic syndrome and the prevention of thromboembolism in patients with nephrotic syndrome. Overviews of the nephrotic syndrome and causes of venous thrombosis as well as the treatment of venous thrombosis are discussed separately:

●(See "Overview of heavy proteinuria and the nephrotic syndrome".)

●(See "Overview of the causes of venous thrombosis".)

●(See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)".)

●(See "Venous thromboembolism: Initiation of anticoagulation".)

●(See "Venous thromboembolism: Anticoagulation after initial management".)

EPIDEMIOLOGY — The incidence of both venous and arterial thrombosis is higher in patients with nephrotic syndrome compared with estimates in the general population [7,8]. In a Danish registry study of 3967 adults with first-time nephrotic syndrome, the one-year absolute risks of arterial and venous thromboembolism were 4 and 3 percent, respectively, and the 10-year absolute risks were 14 and 8 percent, respectively [8]. By comparison, among age- and sex-matched controls, the one-year risks of arterial and venous thromboembolism were 1 and 0.4 percent, respectively, and 10-year risks were 9 and 3 percent, respectively. Among patients with the nephrotic syndrome, the highest 10-year risks were observed with ischemic stroke (8 percent) and myocardial infarction (6 percent).

The risk of venous thromboembolism among patients with other forms of kidney disease appears to be lower than that for patients with nephrotic syndrome but is higher than that for patients without kidney disease. In another Danish registry study that evaluated the risk of thromboembolism among patients with and without kidney disease, the adjusted odds ratio (OR) for venous thromboembolism was 1.41 (95% CI 1.22-1.63) for patients with hypertensive nephropathy, 1.46 (95% CI 1.30-1.64) for those with diabetic nephropathy, 1.48 (95% CI 1.22-1.81) for those with polycystic kidney disease, 2.03 (95% CI 1.76-2.34) for those with glomerulonephritis without nephrotic syndrome, and 2.89 (95% CI 2.26-3.69) for those with nephrotic syndrome [9]. The risk for thromboembolism was most pronounced within the first three months after the diagnosis of kidney disease (adjusted OR 23.23 and 8.64 for nephrotic syndrome and glomerulonephritis, respectively) and decreased thereafter; however, the risk remained elevated even at five years after the diagnosis.

An increase in thromboembolic risk is also present in children with the nephrotic syndrome. (See "Complications of nephrotic syndrome in children", section on 'Thromboembolism'.)

Risk factors for thromboembolism — The risk of thrombosis varies among the causes of nephrotic syndrome and appears to be highest in patients with membranous nephropathy [4,8,10-13]. This was illustrated in a cohort of 1313 patients with idiopathic glomerular disease due to membranous nephropathy, focal segmental glomerulosclerosis, or immunoglobulin A (IgA) nephropathy [10]. The incidence of venous thromboembolic events was much higher in membranous nephropathy (7.9 percent) and focal segmental glomerulosclerosis (3.0 percent) than in IgA nephropathy (0.4 percent). The histologic diagnosis remained a predictive factor for thrombosis after adjustment for the degree of proteinuria (which was much higher at presentation in membranous nephropathy and focal segmental glomerulosclerosis [median 5.6 and 3.7 versus 1.6 g/day in IgA nephropathy]) and the serum albumin concentration.

Patients with membranous nephropathy associated with lupus also appear to be at high risk for thromboembolism. In a study of 66 such patients, venous thromboembolism occurred in 15 (23 percent) at a mean follow-up of 6.9 years [14]. Factors other than nephrotic syndrome can contribute to an increased incidence of thromboembolism in patients with lupus, such as antiphospholipid antibodies. (See "Lupus nephritis: Therapy of lupus membranous nephropathy", section on 'General supportive measures in all patients'.)

An increased risk of thromboembolism has also been reported in patients with minimal change disease [15,16]. As an example, a large case series of 125 patients diagnosed with minimal change disease in adulthood or late adolescence found that arterial or venous thrombosis occurred in 11 (9 percent) [15].

In addition to the cause of nephrotic syndrome, the risk of thrombosis is also related to the severity of hypoalbuminemia and tends to occur early in the course of the disease [4,7,11,12,17-19]. This is particularly true in membranous nephropathy as illustrated in a report of 898 patients with this disorder in the Glomerular Disease Collaborative Network and the Toronto Glomerulonephritis Registry [11]. Mean proteinuria was 7.7 g/day, and the mean serum albumin was 2.6 g/dL (26 g/L).

The following findings were noted:

●Clinically evident and radiologically confirmed venous thromboembolic events occurred in 7.2 percent of patients, which is similar to the 7.9 percent incidence in the study cited above [10].

●The median time to the first thromboembolic event was 3.8 months; 74 percent occurred within the first two years of diagnosis, and 86 percent occurred within three years.

●A low serum albumin concentration at the time of diagnosis, but not the degree of proteinuria, independently predicted a venous thromboembolic event. Compared with patients who had a serum albumin concentration greater than 2.8 g/dL (28 g/L), the risk of an event was significantly higher in patients with a serum albumin concentration ≤2.8 g/dL (28 g/L)—9.4 versus 3.2 percent, adjusted relative risk 2.5. The risk increased by approximately twofold for every 1 g/dL (10 g/L) reduction in serum albumin below this threshold. The duration of hypoalbuminemia (less than or more than six months) was not an independent risk factor for venous thromboembolism.

To assess the absolute risks of venous and arterial thromboembolism, 298 patients with nephrotic syndrome due to primary glomerular disease (minimal change disease, membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis), diabetic nephropathy, or not otherwise specified were followed for a mean of 10±9 years [7]. The annual incidences of venous thromboembolism and arterial thromboembolism were 1.0 and 1.5 percent, respectively, with the highest incidences occurring during the first six months of follow-up (9.9 and 5.5 percent, respectively).

In other causes of the nephrotic syndrome, which are associated with a lower risk of thromboembolism, the risk is particularly increased at a lower serum albumin (below 2.0 g/dL [20 g/L]) in some [17-19] but not all studies [4,12]. In general, low serum albumin levels are a surrogate biomarker for thrombophilia in patients with nephrotic syndrome. It is important to note that serum albumin levels measured by bromocresol green methods may overestimate the serum albumin concentration compared with other methods such as bromocresol purple or immunonephelometry [20].

The possible role of prophylactic anticoagulation in patients with nephrotic syndrome who are at increased risk for thromboembolism is discussed below. (See 'Prevention of thromboembolism' below.)

Deep vein thrombosis — Deep vein thrombosis (DVT) of the extremities is the most commonly observed thromboembolic event in patients with nephrotic syndrome [21,22]. This was illustrated in a review of discharge diagnoses from hospitals in the United States from 1979 to 2005 in which 925,000 patients had a diagnosis of nephrotic syndrome [21]. Among the nephrotic patients, 14,000 (1.5 percent) were diagnosed with DVT while fewer than 5000 had renal vein thrombosis (RVT). The relative risk of DVT was significantly increased (1.72) in nephrotic compared with nonnephrotic patients.

Pulmonary embolism — Pulmonary embolism (PE) has been described in nephrotic patients with or without an evident DVT or RVT [1,4,12,13,17,18,23-25]. The estimated prevalence of asymptomatic PE in patients with the nephrotic syndrome ranges from 12 to over 30 percent, as illustrated in the following findings:

●In a study of 151 consecutive nephrotic patients, 94 underwent ventilation-perfusion lung scan (V/Q scan) [12]. PE was present in 12 patients (13 percent): Five had a PE associated with chronic or acute RVT, and seven had an isolated PE.

●In a series of 89 nephrotic patients with a serum albumin concentration <2.0 g/dL (20 g/L), 19 (21 percent) had a high-probability V/Q scan and, in an additional 25 patients with low or intermediate probability scans, arteriography demonstrated PE in 10 (40 percent) [17].

The risk of symptomatic PE also appears to be increased. In the review cited above of discharge diagnoses from hospitals in the United States, there was a 39 percent increase in PE in nephrotic compared with nonnephrotic patients [21].

Renal vein thrombosis — The epidemiology of RVT is discussed in more detail elsewhere. (See "Renal vein thrombosis in adults", section on 'Epidemiology'.)

PATHOGENESIS — The cause of the hypercoagulable state in patients with nephrotic syndrome is not well understood. Studies evaluating measures of hemostasis activation, such as the plasma level of fibrinopeptide A, which is cleaved from fibrinogen by thrombin, suggest that even asymptomatic nephrotic patients have evidence of ongoing subclinical coagulation [26]. A variety of hemostatic abnormalities have been described, including decreased levels of natural anticoagulants such as plasminogen and protein C and S (due to urinary losses); increased platelet activation; hyperfibrinogenemia; inhibition of plasminogen activation; and the presence of high-molecular-weight fibrinogen moieties in the circulation [2,4,27-31]. Although previous studies suggested that urinary loss of antithrombin III leading to acquired antithrombin deficiency was a potentially important contributing mechanism, an analysis of three independent cohorts of patients with nephrotic syndrome found an inconsistent relationship between antithrombin levels and hypercoagulopathy in nephrotic patients [32].

The tendency to form thrombi at the renal vein in the nephrotic syndrome may be due in part to the loss of fluid across the glomerulus [4]. The ensuing hemoconcentration in the postglomerular circulation, which is worsened by diuretic therapy, may promote thrombus formation in patients who are already hypercoagulable.

PREVENTION OF THROMBOEMBOLISM — The likelihood of benefit from prophylactic anticoagulation is dependent upon three factors: the incidence of thrombotic events, the ability of anticoagulation to prevent such events, and the bleeding risk associated with anticoagulation. (See 'Risk factors for thromboembolism' above and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Complications'.)

No randomized controlled trials have compared the risks associated with undiagnosed venous thrombosis with the risk of long-term anticoagulation in patients with nephrotic syndrome. In a prospective, uncontrolled study, 30 patients with nephrotic syndrome (14 with membranous nephropathy, 13 with focal segmental glomerulosclerosis, median serum albumin 1.7 g/dL [17 g/L], and median protein excretion of 9 g/day) were treated with low-molecular-weight heparin for a median of 13 months [33]. Patients with a serum creatinine >2.3 mg/dL (203 micromol/L) and those who weighed less than 40 kg received one-half the typical prophylactic dose of low-molecular-weight heparin. At baseline, patients had no thromboses, as assessed by Doppler ultrasound of the renal and lower extremity veins and ventilation-perfusion scan (V/Q scan) of the lungs, and reassessment every three months demonstrated no thromboses throughout follow-up. No serious adverse events were reported. Given the small number of patients in this study, however, these findings are insufficient to firmly establish the efficacy of low-molecular-weight heparin in preventing thromboembolism in this patient population.

Because of the lack of randomized trials, the optimal approach to prophylactic anticoagulation in patients with nephrotic syndrome is not well defined. Furthermore, it is unclear if the findings in membranous nephropathy apply to other causes of nephrotic syndrome, since membranous nephropathy is associated with the highest risk of thromboembolic events and similar large series are not available for the other causes. (See 'Risk factors for thromboembolism' above.)

Approach to prophylactic anticoagulation — In general, the risk of thrombosis is inversely related to the serum albumin levels. In particular, patients with membranous nephropathy who have very low serum albumin levels and a low to intermediate risk of serious bleeding may benefit from prophylactic anticoagulation [34-36]. In addition, pregnant patients with nephrotic syndrome, regardless of cause, are at increased risk for venous thromboembolism and may also benefit from prophylactic anticoagulation. Our approach to prophylactic anticoagulation is discussed below (algorithm 1).

Assessment of bleeding risk — In all patients with nephrotic syndrome who do not have a contraindication to anticoagulation (table 1), the decision to prescribe prophylactic anticoagulation must be balanced against the risk of bleeding. When the risk of anticoagulation-associated bleeding is unclear, it can be estimated using various prediction models, including the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk score [37] or the HAS-BLED bleeding risk score (calculator 1). (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Mitigating bleeding risk' and "Risks and prevention of bleeding with oral anticoagulants", section on 'Bleeding risk scores'.)

In general, prophylactic anticoagulation should be avoided in patients who are considered to be at high risk for bleeding.

Patients with membranous nephropathy — As discussed above, patients with membranous nephropathy are at high risk for thromboembolism. Patients who have very low serum albumin levels and a low to intermediate risk of serious bleeding may benefit from prophylactic anticoagulation, even if there are no other reasons for anticoagulation [34-36]. In addition, the presence of other risk factors for thromboembolism may also impact the clinical decision to initiate prophylactic anticoagulation. (See 'Risk factors for thromboembolism' above and "Overview of the causes of venous thrombosis".)

In nonpregnant patients with membranous nephropathy, our approach to prophylactic anticoagulation is based upon the assessed bleeding risk (see 'Assessment of bleeding risk' above) and the serum albumin concentration (algorithm 1). There is no high-quality evidence to support these (or any other) serum albumin thresholds, and these thresholds are largely based upon data from existing observational studies [35,38] as well as our clinical experience:

●If the anticoagulation-associated bleeding risk is high or the serum albumin level is ≥3.0 g/dL, we do not administer prophylactic anticoagulation.

●If the anticoagulation-associated bleeding risk is low and the serum albumin level is <3.0 g/dL, we administer prophylactic anticoagulation with low-molecular-weight heparin or warfarin.

●If the anticoagulation-associated bleeding risk is intermediate and the serum albumin level is <2.0 g/dL, we administer prophylactic anticoagulation with low-molecular-weight heparin or warfarin.

●If the anticoagulation-associated bleeding risk is intermediate and the serum albumin level is between 2.0 and 2.9 g/dL, the decision to administer prophylactic anticoagulation should be made on a case-by-case basis after weighing the benefits and risks of anticoagulation. There are insufficient data in this patient population to support a particular therapeutic approach. Some contributors to this topic would administer prophylactic antiplatelet therapy with aspirin (81 mg once daily). Other contributors would administer low-molecular-weight heparin or warfarin when the serum albumin is between 2.0 and 2.5 g/dL and would not administer prophylactic anticoagulation when the serum albumin is between 2.6 and 2.9 g/dL.

The dosing and duration of prophylactic anticoagulation are discussed elsewhere in this topic. (See 'Dosing and efficacy' below and 'Duration of therapy' below.)

We do not routinely prescribe direct oral anticoagulants (DOACs) as prophylactic anticoagulation in patients with membranous nephropathy, given the limited data evaluating their use in this patient population. The use of DOACs may be considered in patients with side effects or inadequate therapeutic effects from warfarin and if the patient is unwilling to take low-molecular-weight heparin [39]. However, in one case report, a patient with membranous nephropathy developed recurrent venous thromboembolism while receiving therapeutic dosing of the oral factor Xa inhibitor apixaban [40], highlighting the need for additional studies in this high-risk patient population. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

Patients with other causes of nephrotic syndrome — In nonpregnant patients with a cause of nephrotic syndrome other than membranous nephropathy (eg, minimal change disease, focal segmental glomerulosclerosis), our approach to prophylactic anticoagulation is based upon the assessed bleeding risk (see 'Assessment of bleeding risk' above) and the serum albumin concentration (algorithm 1). As with membranous nephropathy, there is no high-quality evidence to support these (or any other) serum albumin thresholds, and these thresholds are largely based upon data from existing observational studies [38] as well as our clinical experience:

●If the anticoagulation-associated bleeding risk is high (see 'Assessment of bleeding risk' above) or the serum albumin level is ≥3.0 g/dL, we do not administer prophylactic anticoagulation.

●If the anticoagulation-associated bleeding risk is low or intermediate and the serum albumin level is <2.0 g/dL, we administer low-molecular-weight heparin or warfarin.

●If the anticoagulation-associated bleeding risk is low or intermediate and the serum albumin level is between 2.0 and 2.9 g/dL, the decision to administer prophylactic anticoagulation should be made on a case-by-case basis. Some contributors to this topic would administer prophylactic antiplatelet therapy with aspirin (81 mg once daily). One contributor would administer low-molecular-weight heparin or warfarin in patients with acute, severe nephrotic syndrome due to minimal change disease, given the higher risk of venous thromboembolism in such patients. (See 'Risk factors for thromboembolism' above.)

The dosing and duration of prophylactic anticoagulation are discussed elsewhere in this topic. (See 'Dosing and efficacy' below and 'Duration of therapy' below.)

We do not routinely prescribe DOACs as prophylactic anticoagulation in patients with a cause of nephrotic syndrome other than membranous nephropathy, given the limited data evaluating their use in this patient population. However, use of DOACs may be considered in patients with side effects or inadequate therapeutic effects from warfarin and if the patient is unwilling to take low-molecular-weight heparin [39]. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

Pregnant patients — Our approach to prophylactic anticoagulation in pregnant women with nephrotic syndrome is similar to that for nonpregnant patients with nephrotic syndrome, which is based upon the assessed bleeding risk and the serum albumin concentration (see 'Assessment of bleeding risk' above and 'Patients with membranous nephropathy' above and 'Patients with other causes of nephrotic syndrome' above). However, since pregnancy is a prothrombotic state, we have a lower threshold for administering prophylactic anticoagulation to prevent venous thromboembolism. There are no studies that have evaluated the benefits or risks of prophylactic anticoagulation in pregnant women with nephrotic syndrome, and our approach is based primarily upon clinical experience:

●If the anticoagulation-associated bleeding risk is high (see 'Assessment of bleeding risk' above) or the serum albumin level is ≥3.0 g/dL, we do not administer prophylactic anticoagulation.

●Regardless of the cause of nephrotic syndrome, if the anticoagulation-associated bleeding risk is low or intermediate and the serum albumin level is <2.5 g/dL, we administer low-molecular-weight heparin.

●If the patient has membranous nephropathy, the anticoagulation-associated bleeding risk is low, and the serum albumin is <3.0 g/dL, we administer low-molecular-weight heparin.

Low-molecular-weight heparin or unfractionated heparin is appropriate for prophylactic anticoagulation in pregnancy. Warfarin should be avoided because it crosses the placenta and can have adverse fetal effects, but can be used postpartum, even in breastfeeding women. DOACs should be avoided during pregnancy and should not be given to women who are breastfeeding. Dosing of anticoagulation and other issues related to the use of anticoagulants during pregnancy and postpartum are discussed in more detail elsewhere. (See "Use of anticoagulants during pregnancy and postpartum".)

Dosing and efficacy — Initial dosing of low-molecular-weight heparin and warfarin for prophylactic anticoagulation in patients with nephrotic syndrome is the same as that used to treat venous thromboembolism in the general population. Low-molecular-weight heparin should be used with caution in individuals whose kidney function is markedly reduced and/or unstable. If used (particularly for a long duration), intermittent monitoring of anti-factor Xa is advised [41]. (See "Clinical use of coagulation tests", section on 'Monitoring heparins' and "Heparin and LMW heparin: Dosing and adverse effects", section on 'Dosing and monitoring'.)

Issues related to the use of heparin in patients with a prior history of heparin-induced thrombocytopenia (HIT) are discussed elsewhere. (See "Venous thromboembolism: Initiation of anticoagulation" and "Venous thromboembolism: Initiation of anticoagulation", section on 'Heparin-induced thrombocytopenia'.)

There are no randomized trials comparing different anticoagulants in the prevention of thromboembolism in patients with nephrotic syndrome. Our approach to prophylactic anticoagulation is based upon observational studies in patients with nephrotic syndrome, most of which have examined warfarin, low-molecular-weight heparin, or aspirin [25,33,38,42]. Of note, these studies did not include pregnant women with nephrotic syndrome.

In a retrospective study of 143 nephrotic patients with minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy, the choice of anticoagulant was determined by the serum albumin. Patients who had a serum albumin of 2.0 to 3.0 g/dL received aspirin (75 mg/day), and those with a serum albumin of less than 2.0 g/dL received low-molecular-weight heparin (enoxaparin at 20 mg subcutaneously once daily) for three months, followed by conversion to warfarin (goal international normalized ratio [INR] 1.5 to 2.5) if the nephrotic syndrome persisted [38]. Two patients (1.4 percent) developed venous thromboembolism within the first week of therapy; after the first week, there were no further venous thromboembolism events. One patient developed gastrointestinal bleeding that required hospitalization, and two with occult bleeding underwent elective transfusion.

There is minimal clinical experience with the newer DOACs. These agents have been used in a few patients with side effects or inadequate therapeutic effects from warfarin and if the patient is unwilling to take low-molecular-weight heparin [39,43]. If a DOAC is selected, careful attention to dose adjustments in the presence of kidney function impairment is required and the potential for drug interactions should be considered. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

Duration of therapy — The optimal duration of prophylactic anticoagulation therapy in patients with nephrotic syndrome is not defined. We continue prophylactic anticoagulation until remission of nephrotic syndrome or when a serum albumin above 3.0 g/dL is achieved, at which time we discontinue anticoagulation therapy if there is no other indication for anticoagulation.

Monitoring during therapy — All patients on anticoagulation should be monitored clinically for therapeutic efficacy, bleeding, as well as the development of conditions that affect the half-life of the medications used (eg, kidney failure, pregnancy, weight gain/loss), and adverse effects of the medications (eg, skin necrosis, thrombocytopenia). Laboratory monitoring varies with the long-term anticoagulant used. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Monitoring'.)

In patients treated with warfarin, the dose should be adjusted to achieve a goal INR between 1.5 and 2.5 [38]. Patients who develop a deep vein thrombosis (DVT)/pulmonary embolism (PE) despite being on warfarin may be considered for DOAC therapy [39]. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Patients with the nephrotic syndrome are at increased risk for venous thrombosis, particularly deep vein thrombosis and renal vein thrombosis, as well as arterial thrombosis. The risk of thrombosis varies among the causes of nephrotic syndrome and appears to be highest in patients with membranous nephropathy (MN). (See 'Epidemiology' above.)

●Pathogenesis – The cause of the hypercoagulable state in patients with nephrotic syndrome is not well understood. A variety of hemostatic abnormalities have been described, including decreased levels of natural anticoagulants such as plasminogen and protein C and S (due to urinary losses); increased platelet activation; hyperfibrinogenemia; inhibition of plasminogen activation; and the presence of high-molecular-weight fibrinogen moieties in the circulation. (See 'Pathogenesis' above.)

●Prevention of thromboembolism – The optimal approach to prophylactic anticoagulation in patients with nephrotic syndrome is not well defined. Our approach is as follows (see 'Prevention of thromboembolism' above):

•Assessment of bleeding risk – In patients with nephrotic syndrome who do not have a contraindication to anticoagulation (table 1), the decision to prescribe prophylactic anticoagulation must be balanced against the risk of anticoagulation-associated bleeding. When the risk of bleeding is unclear, it can be estimated using various prediction models, including the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk score or the HAS-BLED bleeding risk score (calculator 1). In general, prophylactic anticoagulation should be avoided in patients who are considered to be at high risk for bleeding. (See 'Assessment of bleeding risk' above.)

•Patients with membranous nephropathy – For nonpregnant patients with MN, we suggest prophylactic anticoagulation to decrease the risk of venous thromboembolism for the following patient groups (Grade 2C):

-Patients with a low bleeding risk and a serum albumin level <3.0 g/dL

-Patients with a low or intermediate bleeding risk and a serum albumin level <2.0 g/dL

In nonpregnant patients with MN who have an intermediate bleeding risk and a serum albumin level between 2.0 and 2.9 g/dL, there is no consensus regarding the approach to anticoagulation. One contributor to this topic would administer prophylactic antiplatelet therapy with aspirin (81 mg once daily). Other contributors would administer prophylactic anticoagulation when the serum albumin is between 2.0 and 2.5 g/dL and would not administer prophylactic anticoagulation or aspirin when the serum albumin is between 2.6 and 2.9 g/dL. (See 'Patients with membranous nephropathy' above.)

•Patients with other causes of nephrotic syndrome – For nonpregnant patients with a cause of nephrotic syndrome other than MN, a low or intermediate bleeding risk, and a serum albumin of <2.0 g/dL, we suggest prophylactic anticoagulation to decrease the risk of venous thromboembolism (Grade 2C).

In nonpregnant patients with a cause of nephrotic syndrome other than MN who have a low or intermediate bleeding risk and a serum albumin level between 2.0 and 2.9 g/dL, there is no consensus regarding the approach to anticoagulation. Some contributors to this topic would administer prophylactic antiplatelet therapy with aspirin (81 mg once daily). One contributor would administer low-molecular-weight heparin or warfarin in patients with acute severe nephrotic syndrome due to minimal change disease, given the higher risk of venous thromboembolism in such patients. (See 'Patients with other causes of nephrotic syndrome' above.)

•Pregnant patients – In pregnant patients with nephrotic syndrome, regardless of cause, a low or intermediate bleeding risk, and a serum albumin of <2.5 g/dL, we suggest prophylactic anticoagulation (Grade 2C). For pregnant patients with MN, a low bleeding risk, and a serum albumin of <3.0 g/dL, we suggest prophylactic anticoagulation (Grade 2C). Low-molecular-weight heparin is the preferred anticoagulation strategy in pregnant patients. (See 'Pregnant patients' above.)

•Choice of anticoagulant – In patients selected for anticoagulation, we choose either warfarin or low-molecular-weight heparin. We do not routinely prescribe direct oral anticoagulants (DOACs), given the limited data evaluating their use in patients with nephrotic syndrome. However, use of DOACs may be considered in patients with side effects or inadequate therapeutic effects from warfarin and if the patient is unwilling to take low-molecular-weight heparin. Initial dosing and duration of therapy are discussed above. (See 'Dosing and efficacy' above and 'Duration of therapy' above.)