Anticoagulation Therapy in Patients with Primary MN

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

.

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

1. Patients with primary membranous nephropathy (MN)
   are at increased risk for thromboembolic complications, including venous thromboembolic
   events (VTEs).
2. 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.
3. 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.