Editorial

Venous Thromboembolism and Membranous

Nephropathy: So Whats New?
Jai Radhakrishnan

Clin J Am Soc Nephrol 7: 34, 2012. doi: 10.2215/CJN.11791111

The association of venous thromboembolism (VTE)

with the nephrotic syndrome, particularly deep vein
and renal vein thrombosis (DVT and RVT, respectively) is
rmly established (13). In a retrospective study of 298
nephrotic patients followed for a mean period of 10 years
(4), the annual incidence of VTE was 1.02%/yr, and the
absolute risk of arterial thrombosis was 1.48%/yr. The
risk of both venous and arterial thrombosis was particularly high within the rst 6 months of diagnosis (with
annual incidences of 9.85% and 5.52%, respectively) (4).
In children with the nephrotic syndrome, 9.2% of 326
patients experienced 38 thromboembolic episodes
over a median period of 3.7 years (5). This risk is particularly high in patients with idiopathic membranous
nephropathy.
Deep vein thrombosis (DVT) of the lower extremities
is the most commonly observed site of thrombosis. In
review of hospital discharges from 1979 to 2005, of
925,000 patients with a diagnosis of nephrotic syndrome, 14,000 (1.5%) were diagnosed with DVT; ,5000
had RVT (6). Pulmonary embolism (PE) has been previously described in nephrotic patients with or without
an evident DVT or RVT (1,7). In a study of 89 nephrotic
patients with a serum albumin ,2.0 g/dl (20 g/L), 19
(21%) patients had a high probability V/Q scan, and, in
patients with low or intermediate probability scans, pulmonary angiograms demonstrated PE in another 10
patients (8,9). The renal vein is a classic site for thrombosis in nephrotic patients, being unusual in healthy subjects, and the prevalence of RVT can vary from 22% to
52% (2,7,10). Acute RVT is uncommon, with chronic
RVT being predominant. Chronic RVT is insidious, usually discovered incidentally or when a workup for the
source of pulmonary embolism reveals it. Although it
has been suggested that a chronic RVT may lead to worsening proteinuria or kidney function, this has never
been clearly documented (10). In a single case report
of a patient with unilateral RVT and nephrotic syndrome
due to membranous nephropathy, bilateral ureteral catheterization studies showed no difference in protein excretion or creatinine clearance between the two kidneys (11).
The reason(s) underlying the hypercoagulable state in
nephrotic patients are not clearly understood. There is
evidence of ongoing subclinical coagulation using measures of hemostasis activation, such as the plasma level of
brinopeptide A (9) and D-dimer. Multiple hemostatic
abnormalities have been described, including decreased
www.cjasn.org Vol 7 January, 2012

levels of antithrombin and plasminogen (due to urinary

losses), increased platelet activation, hyperbrinogenemia, inhibition of plasminogen activation, and
the presence of high-molecular-weight circulating brinogen moieties (9). The possibility of immune complex
injury in the glomerulus resulting in systemic effects on
clotting has also been evoked (9).
The risk of thrombosis seems to be related to the
severity and duration of the nephrotic state and seems to
be particularly increased with serum albumin concentrations #2.0 g/dl (20 g/L) (9). Furthermore, among the
causes of nephrotic syndrome, the risk is highest with
membranous nephropathy, followed by membranoproliferative GN and minimal change disease (9).
The diagnosis of thrombotic complications is usually
based on clinical suspicion and conrmed by the appropriate imaging study (CT angiogram, nuclear scans, and
ultrasound/Doppler scans). Whether asymptomatic patients should be screened is not clear because there is an
absence of studies that show clinical benet from screening. Besides, if there is an initially negative study, patients
could conceivably develop thrombosis at a later stage.
The role of prophylactic anticoagulation (especially
in patients with membranous nephropathy with severe
nephrosis) has been debated (12). Using Markov modeling, Sarasin and Schifferli (13) have calculated that
the mortality benet of prophylactic anticoagulation
outweighs the risk. In the authors opinion, prophylactic anticoagulation is suggested in patients with massive proteinuria, a serum albumin ,2.0 g/dl (20 g/L),
and an additional risk factor for thrombosis (e.g., a
prior idiopathic thromboembolic event; immobilization; severe heart failure; morbid obesity; or abdominal, orthopedic, or gynecologic surgery). Patients who
achieve remission of nephrotic syndrome should have
anticoagulation discontinued 6 months after remission
if there is no other indication for anticoagulation (9).
In the article by Lionaki et al in this issue of CJASN
(14), the largest ever reported cohort (n5898) of patients with membranous nephropathy was analyzed
for the incidence of thromboembolic events and predisposing factors contributing to this risk. The main
messages from this paper were the relatively low(er)
risk for VTE of 7.2% compared with some earlier studies,
the fact that most episodes occur within the rst 2 years
(median time, 3.8 months from diagnosis of nephrosis),
and the serum albumin supersedes urinary protein with

Department of
Medicine, Division
of Nephrology,
Columbia University
College of Physicians
and Surgeons,
New York, New York
Correspondence:
Dr. Jai Radhakrishnan,
Department of
Medicine, Division
of Nephrology,
Columbia University
College of Physicians
& Surgeons,
New York, NY 10032.
Email: jr55@
columbia.edu

Copyright 2012 by the American Society of Nephrology

Clinical Journal of the American Society of Nephrology

respect to risk. This retrospectively studied cohort of adult

patients was assembled from two North American tertiary
care centers with large populations of glomerular patients
and represented only idiopathic membranous nephropathy.
There were some baseline differences in the two cohorts reecting the populations and practices of the respective institutions. About one-half of the patients were on antiplatelet
agents at the time of VTE (suggesting that these agents might
not provide protection). The good news is that VTE did not
adversely affect renal survival, and no patient died as a consequence of VTE (actual patient survival data with and without VTE are not shown).
In this study, the diagnosis of VTE was made with the
appropriate scanning technique, which was performed when
there was a clinical suspicion (i.e., routine screening was not
performed). This likely led to the lower incidence of VTE
(7.2%) compared with previous studies where RVT could be
seen in up to 50% of patients and pulmonary emboli in 22% of
patients who underwent prospective screening. However,
there are no randomized trials looking at whether prospective
screening leads to a better outcome.
The authors report that the risk of VTE begins at a threshold
albumin of 2.8 g/dl and becomes higher as the albumin levels
drop further. What was surprising was that VTE appeared
early in the course of disease and was not related to the duration
of hypoalbuminemia but to the level of serum albumin. This implies that there are as-yet unidentied patient-specic factors
that, in addition to low albumin levels, confer the VTE risk.
There are several strengths to this study. The major strength
of the study is that this is the largest such cohort assembled
as a consequence of collaboration between two major institutions in North AmericaThe Glomerular Disease Collaborative Networks (from the University of North Carolina, Chapel
Hill, NC) and the Toronto Glomerulonephritis Registry
(from the University of Toronto, Toronto, Canada). The authors have done an admirable job in collecting and analyzing VTE episodes and risk factors in a diverse group of
patients. The VTE rate of 7%8% was remarkably similar in
the two cohorts, supporting the validity of their results. However, there are several limitations to the study. This study
being of retrospective design, it is possible that all cases of
VTE were not captured and that all risk factors were not systematically investigated. For example, likely due to small
sample sizes (and possible under-reporting), protection
from antiplatelet agents and risk from malignancies and
smoking do not seem to be signicant factors. Furthermore,
recurrent VTE rates and response to anticoagulation are not
mentioned. It is surprising that RVT was the predominant
form of VTE (because these are clinically silent in the majority),
which suggests that both clinical diagnosis and screening
were used to dene the patients with VTE (only 10 patients
had VTE in at least one site).
In summary, although not much novel information is
provided in the paper by Lionaki et al., due to the large sample
size, it does serve to provide a better estimate and time of
diagnosis of clinically manifest VTE events in patients with

idiopathic membranous nephropathy. The serum albumin

levels appear to be the pre-eminent risk factor. However, the
single most important question in these patients is whether to
anticoagulate prophylactically or not, and disappointingly,
this was not addressed by the paper (but the authors promise
this decision analysis is underway!).
Disclosures
None.

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Published online ahead of print. Publication date available at www.
cjasn.org.
See related article, Venous Thromboembolism in Patients with
Membranous Nephropathy, on pages 4351.