Primary membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults. Therapy for primary MN focuses on the prevention of end-stage renal disease (ESRD). ESRD commonly occurs several years following presentation with primary MN; however, other complications may occur much earlier in the course of the disease.
Early complications of primary MN include venous thromboembolic events (VTEs) such as deep venous thrombosis (DVT), renal vein thrombosis (RVT), and pulmonary embolism (PE). These complications are associated with significant morbidity and mortality. Hypoalbumineia is the most significant indicator of risk of VTE. Patients with primary MN also experience increased high absolute risk of arterial thromboembolic events (ATEs) within 6 months of presentation. Predictors of ATEs include severe proteinuria, estimated glomerular filtration rate, and smoking. Primary cardiovascular events include acute coronary syndrome (ACS) and ischemic stroke (IS).
Given the need to carefully manage anticoagulants and antiplatelet agents and to tailor therapeutic regimens to an individual’s risk of thromboembolic events, the 2012 Kidney Diseases Improving Global Outcomes (KDIGO) evidence supporting prophylactic and therapeutic anticoagulation is, according to researchers, too weak to meet the needs of primary MN patients with hypoalbuminemia. Honghong Zou and Yebei Li, PhD, conducted a review to provide suggestions to help guide decision making on the management of anticoagulation in patients with primary MN at high risk of thrombosis or with thromboembolic complications. Results of the review were reported online in BMC Nephrology
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The researchers extracted relevant studies by searching the Cochrane Library, Medline, PubMed, and Web of Science from March 1968 to March 2018. Eligible publications included guidelines, reviews, case reports, and clinical trial studies regarding the rational management of anticoagulation therapy in the primary MN population.
The review demonstrated that the risk of thromboembolic events is particularly high in primary MN when compared with other pathological types of nephrotic syndrome and that most patients remain asymptomatic. This finding suggests considering the prophylactic use of anticoagulants or antiplatelet agents to prevent VTEs and ATEs in this patient population. The findings also suggest that the rational management of therapeutic anticoagulation and antiplatelet agents in patients with primary MN and thromboembolic complications may result in the reduction in the risk of recurrent cardiovascular events.
Low serum albumin is a strong independent risk factor for VTEs in patients with primary MN. The increasing risk was proportionally associated with declining albumin levels in a retrospective study accessed by the review. There was an association between each 1.0-g/dL increase in albumin level and a 2.13-fold increase risk of VTE. The study identified the threshold albumin level for the overall risk of VTEs as 2.8 g/dL (i.e., a serum albumin level <2.8 g/dL indicated a high risk of a VTE). In another study, anticoagulation was indicated in patients with primary MN who initially presented with thrombotic events due to the high risk of thromboembolic complications. However, the use of prophylactic anticoagulation therapy remains controversial in primary MN.
The 2012 KDIGO guidelines indicate that prophylactic oral warfarin can be considered in primary MN patients when serum albumin is <2.5 g/dL in the presence of additional risks for thrombosis; some physicians believe prophylactic anticoagulation should be initiated earlier. Studies have shown that aspirin has a therapeutic benefit for the prevention and recurrence of VTEs and significantly reduces the rate of major vascular events with no apparent increase in the risk of major bleeding. Some of the researchers in the reviewed studies felt that patients with primary MN could receive antiplatelet agents such as aspirin for the primary prevention of thrombotic events at an early stage of the disease.
The studies also indicated that the benefits of anticoagulation in the prevention of VTEs should be weighed against the risk of hemorrhage complications in individual patients. Researchers in one study developed a Markov-based decision analysis model to estimate the possibility of benefit based on an individual’s bleeding risk profile, serum albumin level, and acceptable benefit-to-risk ratio.
The treatment regimen for thromboembolic complications in patients with primary MN was similar to that in patients in the general population with thromboembolic events. D-dimer level may be affected by proteinuria and may not be an independent predictor of stopping anticoagulant therapy in patients with primary MN and VTEs. Further, the reduction of proteinuria and the increase of serum albumin are important goals for the treatment of primary MN with VTEs. Clinicians should continue the previous steroid therapy or combine it with immunosuppressive agents over the entire treatment period until the primary MN treatment protocol is completed. There are no clinical trial data regarding the optimal length of anticoagulation therapy in this patient population; one potential approach is to treat patients with anticoagulation therapy at least 3 to 6 months (if there are no contraindications) until serum albumin levels normalize and patients achieve remission.
The researchers cited some limitations to the review, including the majority of the evidence for prophylactic anticoagulation recommendations being derived from retrospective studies.
“The utility of prophylactic aspirin or warfarin may have clinical benefits for the primary prevention of thromboembolic events in primary MN patients with hypoalbuminemia,” the researchers said. “It is necessary to perform large randomized controlled trials and to formulate relevant guidelines to support the present review,” they added.
Takeaway Points
- Patients with primary membranous nephropathy (MN) are at increased risk for thromboembolic complications, including venous thromboembolic events (VTEs).
- Researchers conducted a literature review to provide suggestions on decision making regarding anticoagulant management in patients with primary MN at high risk of thrombosis or with thromboembolic complications.
- The use of prophylactic aspirin or warfarin may have clinical benefits for the primary prevention of thromboembolic events in patients with primary MN with hypoalbuminemia.
