commentary

21 ATEs were observed during the

Should aspirin be used for follow-up period of 52 months (esti-
primary prevention of mated event rate 9 per 1000 py). Risk of
ATE was evidently associated with the
thrombotic events in patients presence of hypoalbuminemia.
The mechanisms leading to a
with membranous hypercoagulation state in NS are
incompletely understood. The risk of
nephropathy? VTEs is attributed to increased pro-
Julia M. Hofstra1 and Jack F.M. Wetzels1 duction of fibrinogen and the urinary
loss of pro- and anticoagulant proteins
Patients with nephrotic syndrome are at increased risk of thrombosis. resulting in lower levels of proteins such
as antithrombin III. The risk of ATEs is
The risk of venous thrombosis is particularly high in patients with attributed to the increased platelet
nephrotic syndrome due to primary membranous nephropathy. activation and aggregation, which has
Recent data provide evidence that these patients also have a high been observed in patients with NS.7
absolute risk of arterial thrombotic events, which is associated with This increased aggregation may result
the degree of hypoalbuminemia. In this commentary we discuss from the loss of proteins that inhibit
whether prophylactic aspirin therapy might be indicated in this platelet formation or platelet aggrega-
tion. Indeed, in vitro experiments have
patient population. shown that addition of proteins found
Kidney International (2016) 89, 981–983; http://dx.doi.org/10.1016/j.kint.2016.01.019 in the urine of nephrotic patients at-
Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved. tenuates platelet aggregation. Plasma
see clinical investigation on page 1111 levels of 1 such protein—PACAP (pi-
tuitary adenylate cyclase–activating

P
atients with nephrotic syndrome
(NS) are at increased risk of
thrombosis. Already in the early
1980s it was noted that the risk of venous
thrombotic event (VTE) and associated
pulmonary embolism was particularly
high in patients with NS due to primary
membranous nephropathy (MN). These
early observations were confirmed in a
recent study in a large cohort of 1313
patients with primary glomerulone-
phritis, showing that risk for VTEs was
markedly higher in patients with MN
(adjusted hazard ratio 10.8) compared to
patients with IgA nephropathy, after
adjustment for baseline characteristics.1
The risk of an event was related to the
level of serum albumin.2 Based on these
observations, current guidelines suggest
the use of prophylactic warfarin in pa-
tients with MN and serum albumin
levels <2.5 g/dl.3 Obviously, in individ-
ual patients the benefits of warfarin in
1
Radboud University Medical Centre, Department
of Nephrology, Nijmegen, the Netherlands
Correspondence: Jack F.M. Wetzels, Radboud
University Medical Centre, Department of
Nephrology 464, PO Box 9101, 6500HB Nijmegen,
the Netherlands. E-mail: jack.wetzels@
radboudumc.nl
preventing VTEs must be weighed
against the risk of bleeding complica-
tions. A Web-based tool has been intro-
duced especially for patients with
primary MN, that enables the physician
to balance risks and benefits (www.
gntools.com).4
Next to VTE, patients with NS might
also be at risk of arterial thrombotic
events (ATEs). In a relatively small
patient cohort, Mahmoodi et al.
showed that patients with NS indeed had
high absolute risks of both venous and
arterial thrombotic events.5 Lee et al.6
(2016) now provide novel data on the
incidence of and risk factors for ATEs in
patients with MN. The authors evaluated
the data of 404 patients from the
Glomerular Disease Collaborative
Network (GDCN) cohort and of 557
patients from the Toronto Glomerulo-
nephritis Registry (TGNR) cohort.
Notably, patients in the TGNR were
younger, more frequently of Asian
descent, had better-preserved kidney
function, and less often had NS. Patients
in the GDCN cohort were followed over
24 months, and ATEs occurred in 31
(estimated event rate 38 per 1000
patient-years [py]). In the TGNR cohort
polypeptide), an inhibitor of platelet
activation—were shown to be inversely
correlated with platelet aggregation in
response to collagen.
The study of Lee et al.6 is important
in drawing attention to the fact that
end-stage kidney disease should not be
the only end point in clinical trials of
MN. In fact, in patients with MN and
preserved kidney function the risk of
ATEs readily exceeded the risk of end-
stage kidney disease. Risk of ATEs was
particularly high in the period of NS,
thus explaining the higher incidence of
ATEs in the first 2 years after presen-
tation. It is well known that in patients
with MN proteinuria decreases with
time of follow-up, as a consequence of
either disease progression or disease
remission. Approximately two-thirds of
patients will reach this end point within
2 years and almost all within 5 years
after presentation. Other risk factors for
ATEs were age, diabetes, and a previous
history of ATEs.
The retrospective nature of the study
is a limitation, with details lacking on
the use of aspirin, statins, angiotensin-
converting enzyme inhibitors, and
immunosuppressive drugs. Notably,

Kidney International (2016) 89, 976–987 981

commentary
apparently prophylactic warfarin ther-
apy was not used in the study period.
Therefore, it is unclear whether the re-
ported incidence rates are applicable to
patients with MN treated according to
the current guidelines. Unfortunately,
the study also did not include patients
with NS due to other glomerular dis-
eases; it therefore remains unknown
whether risk of ATE, like risk of VTE, is
higher in patients with MN than in
patients with NS due to other glomer-
ular diseases. Unexpectedly, the authors
did not establish estimated glomerular
filtration rate as risk factor. This likely
represents bias, since estimated
glomerular filtration rate is a well-
recognized risk factor of ATEs in pa-
tients with chronic kidney disease as
well as in the overall population.
Another remarkable finding received
too little attention: the risk of ATEs was
markedly lower in the TGNR cohort
than in the GDCN cohort (relative risk
0.5), after adjustment for clinical risk
factors associated with ATEs. A more
detailed comparison of conservative
treatment, lifestyle, and dietary habits
between the 2 cohorts might have
revealed interesting clues. One impor-
tant difference is notable: the use of
corticosteroids was much higher in
the GDNC than in the TGNR cohort
(76% vs. 50%). This brings to mind the
studies that have pointed to the pro-
thrombotic effects of prednisone.8
Current treatment guidelines suggest
that immunosuppressive therapy
should only be used in patients with
high risk of end-stage renal disease.
Therefore, many patients are followed
with close observation and maximal
conservative therapy for 1 to 2 years. It
is important to realize that complica-
tions can occur in this phase, VTEs,
ATEs, and infections being the most
frequent. Preventing these complica-
tions may improve patient outcome.
Therefore, it seems attractive to
consider the prophylactic use of aspirin
to prevent ATEs in patients with MN
and NS. In this era of evidence-based
therapy, a randomized controlled trial
that evaluates the benefits of early
aspirin therapy in patients with MN
would be preferred. However, a crude
982
power calculation shows that such a the data suggest that the risk of ATEs
trial should include more than 6000 exceeds 20 per 1000 py in most patients
patients, an impossible endeavor. with MN and a serum albumin <3.2
Efficacy and risks of aspirin therapy g/dl, with the possible exception of the
in secondary and primary prevention very young, non-smoking patient with
trials have been described.9 The risks of well-preserved kidney function.
aspirin (0.1% risk of a major bleeding Thus, is it time to consider aspirin
complication) are considered too high to therapy in patients with MN and NS?
balance the benefit of a 25% risk The decision to start aspirin could be
reduction in a general population with a guided by an algorithm as depicted in
baseline ATE risk of 5 per 1000 py. In Figure 1. It is evident that prophylactic
contrast, aspirin is of proven benefit in warfarin should be used in patients with
secondary prevention trials, where base- serum albumin <2.5 g/dl and low
line risk is approximately 70 per 1000 py. bleeding risk. It is important to realize
If we accept a benefit–risk ratio of 4:1, that 43% of patients with a VTE in the
prophylactic therapy seems acceptable in study of Lionaki et al.2 were on aspirin
a population with an absolute ATE risk when the VTE developed. However,
of 20 per 1000 py. In the overall GDCN in patients with high bleeding risk
cohort event rates in the first year after (www.gntools.com) and in patients
diagnosis exceeded this figure, with a with NS, but low calculated VTE risk,
cumulative incidence of ATE event of aspirin therapy might be offered. In
2.6% at 1 year in patients with estimated view of the potential prothrombotic
glomerular filtration rate >60 ml/min effects of corticosteroids, it is important
per 1.73 m2 and of 7.1% in patients with that the decision to start immunosup-
estimated glomerular filtration rate <60 pressive therapy (often including high-
ml/min per 1.73 m2. In contrast, the dose prednisone) should not lead to
cumulative incidence of ATEs was only postponement of the start of aspirin.
1.1% at 1 year in the TGNR cohort Obviously, a strategy as proposed
(equaling 11 per 1000 py). Still, if we would need additional data. More
factor in severity of NS (hazard ratio 2.4) studies are needed to allow calculation of
and age (hazard ratio 1.6 per decade), the absolute ATE risk in the individual
Figure 1 | Algorithm to guide the decision on primary prevention of venous and arterial
thrombosis in patients with primary membranous nephropathy. ATE, arterial thrombotic
event; eGFR, estimated glomerular filtration rate; NS, nephrotic syndrome; py, patient-years;
VTE, venous thrombotic event. #The Framingham Risk Score includes age, smoking, serum
cholesterol, and blood pressure. *Additional data are needed to calculate specific, attributed
risk of nephrotic syndrome.
Kidney International (2016) 89, 976–987

patient, based on clinical characteristics.
With respect to efficacy and risks, it
would be advisable to consider collecting
large-registry data and comparing out-
comes such as ATEs using propensity
scoring methodology. A large interna-
tional, collaborative network merging
existing databases should be considered.
DISCLOSURE
All the authors declared no competing
interests.
REFERENCES
1. Barbour SJ, Greenwald A, Djurdjev O, et al. Disease-
specific risk of venous thromboembolic events
is increased in idiopathic glomerulonephritis.
Kidney Int. 2012;81:190–195.
2. Lionaki S, Derebail VK, Hogan SL, et al. Venous
thromboembolism in patients with membranous
nephropathy. Clin J Am Soc Nephrol. 2012;7:43–51.
3. Kidney Disease: Improving Global Outcomes
(KDIGO) Glomerulonephritis Work Group.
KDIGO Clinical Practice Guideline for
Glomerulonephritis. Kidney Int Suppl. 2012;2(2).
Buyer beware transplantation
Jeremy R. Chapman1 and Francis L. Delmonico2
Poor long-term outcomes of commercial transplantation of transplant
tourists reinforce the need to prevent this form of human trafficking.
The development of an International Convention by the Council of
Europe is highlighted and the implications for physicians of the
criminalizing of organ trafficking are considered. The causes of poor
outcomes from transplant tourism are considered, with the actions
needed to provide both equity and sufficiency of access to
transplantation as critical deterrent measures.
Kidney International (2016) 89, 983–985; http://dx.doi.org/10.1016/j.kint.2016.01.021
Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
see clinical investigation on page 1119
I
n this issue, Prasad et al.1 (2016)
review the 8-year outcomes of a
group of 69 patients who received 72
commercial kidney transplants and
1
Department of Medicine and Cancer, Westmead
Hospital, Sydney, New South Wales, Australia; and
2
Department of Surgery, Harvard Medical School
at the Massachusetts General Hospital, Boston,
Massachusetts, USA
Correspondence: J.R. Chapman, Department of
Medicine and Cancer, Westmead Hospital, Syd-
ney, New South Wales 2145, Australia. E-mail:
Jeremy.chapman@sydney.edu.au
Kidney International (2016) 89, 976–987
4. Lee T, Biddle AK, Lionaki S, et al. Personalized
prophylactic anticoagulation decision analysis
in patients with membranous nephropathy.
Kidney Int. 2014;85:1412–1420.
5. Mahmoodi BK, ten Kate MK, Waanders F, et al.
High absolute risks and predictors of venous
and arterial thromboembolic events in
patients with nephrotic syndrome: results
from a large retrospective cohort study.
Circulation. 2008;117:224–230.
6. Lee T, Derebail VK, Kshirsagar AV, et al.
Patients with primary membranous
nephropathy are at high risk of cardiovascular
events. Kidney Int. 2016;89:1111–1118.
7. Eneman B, Levtchenko E, van den Heuvel B,
et al. Platelet abnormalities in nephrotic
syndrome [e-pub ahead of print]. Pediatr
Nephrol. http://dx.doi.org/10.1007/s00467-
015-3173-8, accessed August 13, 2015.
8. Ueda N. Effect of corticosteroids on some
hemostatic parameters in children with
minimal change nephrotic syndrome.
Nephron. 1990;56:374–378.
9. Antithrombotic Trialists’ Collaboration,
Baigent C, Blackwell L, Collins R, et al. Aspirin in
the primary and secondary prevention of
vascular disease: collaborative meta-analysis of
individual participant data from randomised
trials. Lancet. 2009;373:1849–1860.
returned to their Canadian center for
follow-up. It is known that short-term
outcomes from commercial transplants
are poor—with well-documented sub-
stantial surgical and infection risks2—
without enumerating the unknown
early mortality of recipients who never
return from surgery. In this paper, the
longer term risks for medical tourist
recipients of commercial transplants
were compared to 1529 domestic
Canadian transplant recipients from
that center and shown to include excess
commentary
delayed graft function, poor long-term
renal function and poor death-
censored graft survival. Of the 69
patients, 5 sero-converted to hepatitis
C, and 2 to hepatitis B; 2 developed
tuberculosis, in addition to the previ-
ously documented wound infections,
fungal sepsis, and a cerebrospinal
abscess.3 A multivariate Cox regres-
sion model demonstrated commercial
transplantation, delayed graft function,
and estimated glomerular filtration
rate <30 ml/min/1.73 m2 at 3 months
to be independent risk factors for
death-censored allograft survival to
8 years. Death and graft failure was
twice as common in commercial
versus domestic transplants. Transplant
tourism4 represented between 3 and 6
transplants per year in the period from
1998 to 2013, or a little less than 5% of
kidneys transplanted and followed at
this center over the same period. The
operations were predominantly per-
formed in a variety of countries in Asia,
though Africa, Latin America, and
Europe were also documented, in
accord with other estimates of the
volume and origin of commercial organ
transplantation.5
Prasad et al.1 thus provide specific
long-term data to inform individuals
contemplating transplant tourism.
There is another international devel-
opment that provides a compelling
emphasis on the risks of the practice
based on criminal illegality, defined by
the Council of Europe Convention
against Trafficking in Human Organs
(CoEC).6 The CoEC calls on govern-
ments to establish as a criminal offense
the illegal removal of human organs
from living or deceased donors:
 where the removal is performed
without the free, informed, and spe-
cific consent of the living or deceased
donor, or, in the case of the deceased
donor, without the removal being
authorized under national domestic
law;
 where, in exchange for the removal of
organs, the living donor, or a third
party, receives a financial gain or
comparable advantage;
 where, in exchange for the removal of
organs from a deceased donor, a third
983