Nephrology Dialysis Transplantation 2007 22(Supplement 1):i17-i22; doi:10.1093/ndt/gfm089
© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Kaposi's sarcoma in renal transplant recipients—the impact of proliferation signal inhibitors
Josep M. Campistol1 and
Francesco P. Schena2
1Department of Nephrology, Hospital Clínic, University of Barcelona, 08036 Barcelona, Spain and 2Division of Nephrology Dialysis and Transplantation, Policlinico, 70124 Bari, Italy
Correspondence and offprint requests to: J. M. Campistol, Servei de Nefrologia i Transplantament Renal, Renal Transplant Unit, Hospital Clínic, Universitat de Barcelona, 170, Villarroel, 08036 Barcelona, Spain. Tel: +34 93 227 54 23; Fax: +34 93 227 54 98; Email: jmcampis{at}clinic.ub.es
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Abstract
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The incidence of Kaposi's sarcoma (KS) is greatly increased
in renal transplant recipients compared with the general population,
with particular prevalence in certain ethnic groups where it
can occur in up to 5% of transplant recipients. The increased
incidence of disease in transplant populations may, in part,
be attributed to the choice of immunosuppressive regimen, with
calcineurin inhibitor (CNI)-based immunosuppression being associated
with the development of the tumour. A number of small studies
have recently demonstrated that conversion to proliferation
signal inhibitors (PSIs) along with the concomitant withdrawal
of CNIs leads to a rapid resolution of both cutaneous and visceral
Kaposi's lesions. In agreement with these data the abrupt onset
of KS has been observed following the withdrawal of PSIs. Histological
examination of lesions from patients with KS supports data from
animal models which suggests that PSIs inhibit tumour angiogenesis
through impaired vascular endothelium growth factor production,
a key element in the development of the tumour. Previously unpublished
data on renal transplant recipients from a number of European
and Australian centres have been pooled to provide further insight
into the use of PSIs in the management of post-transplant KS.
Both members of the PSI class, everolimus and sirolimus, along
with CNI withdrawal lead to regression of KS lesions in 11 out
of 12 patients. Conversion to PSIs was generally well tolerated
with stable renal function maintained in most patients and no
episodes of acute rejection recorded. PSIs provide a potential
treatment option in the management of post-transplant KS and
should be considered for use in renal transplant recipients
who develop the disease.
Keywords: Kaposi's sarcoma; post-transplant malignancy; proliferation signal inhibitors/mammalian target of rapamycin inhibitors; renal transplant recipients
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Introduction
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Kaposi's sarcoma (KS) is a skin tumour of multicentric origin,
characterized histologically by endothelium-lined vascular spaces
and spindle-shaped cells [
1]. KS presents as single or multiple
lesions on mucosal surfaces, including the skin, lungs, gastrointestinal
tract and lymphoid tissue [
1,
2]. This article reviews the increased
risk and pathogenesis of KS post-transplantation, specifically
highlighting the impact of immunosuppressive regimens in renal
transplant recipients. In particular, data suggest a potential
role for proliferation signal inhibitors (PSIs; also known as
mammalian target of rapamycin inhibitors) everolimus (Certican®,
Novartis Pharma AG, Basel, Switzerland) and sirolimus (Rapamune®,
Wyeth Pharmaceuticals, USA) in the management and prevention
of KS.
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Pathogenesis
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KS is seen as both an endemic disease in African and Mediterranean
populations, and as an epidemic disease associated with human
herpes virus (HHV) 8 [
3]. In healthy adults, HHV-8 infection
is not associated with any specific, severe illness, although
reported symptoms at the time of seroconversion in infected
individuals include transient lymphadenopathy, diarrhoea, fatigue
and skin rash [
4]. Control of infection in healthy individuals
appears to be mediated via an antiviral T-cell response to viral
lytic proteins [
4]. The development of KS is thought to be associated
with reactivation of HHV-8 in transplant recipients, however,
reactivation of the virus does not confirm development of the
disease, as observed in the United States, where prevalence
of KS in solid organ transplant recipients was 0.5%, lower than
the estimated 20% rate of HHV-8 [
1]. The mechanism through which
KS develops is unclear [
5], although recent evidence suggests
that development involves initial latent HHV-8 infection of
endothelial cells and subsequent conversion to spindle cells
[
6]. This is followed by a proliferative phase and expression
of a lytic cycle protein, viral G-protein–coupled receptor
(vGPCR). In endothelial cells, the vGPCR oncoprotein increases
the secretion of vascular endothelial growth factor (VEGF) and
up-regulation of its receptor, fetal liver kinase-1/kinase domain
receptor (Flk-1/KDR). This activation, along with other paracrine
events, plays a pivotal role in the development of the final
tumour [
6].
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Epidemiology
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The epidemiological profile of KS in transplant recipients is
summarized in
Table 1. The majority of cases of KS occurs in
patients from Mediterranean, Jewish, Arabic, Caribbean or African
ethnic groups [
2,
7]. The incidence of KS in transplant recipients
may be as high as 500 times that in healthy individuals [
2,
7].
KS often occurs early after transplantation with the time to
the onset of disease ranging from 5 to 21 months post-transplant
[
1,
2,
5,
7], however, it has been reported as late as 18 years
post-transplant [
7]. The prevalence of KS in transplant recipients
varies depending on geographical location, ranging from 0.5%
in Western countries, such as the USA, to 5.3% in Saudi Arabia
[
7].
The effects of specific immunosuppressive agents on the incidence
of KS has also been evaluated, with ciclosporin (CsA)-based
regimens appearing to be associated with a higher incidence
of the tumour than those based on azathioprine [
2]. Moreover,
reports suggest that KS in patients receiving CsA is more severe
than that in patients receiving azathioprine [
8]. An association
between KS and low-dose corticosteroids has also been observed
by some authors, with Vincent
et al. [
9] reporting KS in two
elderly women receiving treatment for rheumatological disease.
Reduction or discontinuation of immunosuppression is generally
the first step in managing KS, balancing likely loss of the
graft from rejection against loss of life from KS. Therefore,
conversion to alternative immunosuppressive agents is an attractive
option. Conversion from CsA to low therapeutic doses of mycophenolate
mofetil (MMF), for example, may lead to regression of KS [
10,
11].
The proliferation signal inhibitors (PSIs) sirolimus and everolimus,
however, may, through specific effects on VEGF, provide the
greatest promise as immunosuppressive agents with anti-neoplastic
activity [
12].
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Conversion to proliferation signal inhibitors
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The potential role for sirolimus in the management of post-transplantation
KS was first noted by Campistol
et al. [
6], in a report on two
renal transplant recipients with KS who underwent complete regression
after conversion to sirolimus. Both patients presented with
multiple cutaneous KS while receiving CsA-based immunosuppression.
The first patient was converted from CsA and MMF to sirolimus
(3 mg/day), with resolution of the lesions within 3 months.
In the second patient, continuation of CsA and withdrawal of
azathioprine and prednisone had no effect on the lesions. Additional
reductions in CsA dose led to no alteration in the existing
lesions, and no new lesions, over 6 years. The patient was eventually
converted to sirolimus (3 mg/day), with gradual disappearance
of the lesions 2 months later. Both patients maintained good
renal function after conversion [
6]. The following year, a number
of reports of KS regression in renal transplant recipients were
published. Gutíerrez-Dalmau
et al. [
13] carried out a
retrospective chart review of seven patients with cutaneous
KS. After conversion to sirolimus from calcineurin inhibitor
(CNI) therapy, six patients showed regression of their lesions
in a mean time of 8.1 months, with the seventh patient showing
almost complete regression after 9 months. Renal function was
maintained in six patients, with acute renal failure unrelated
to sirolimus reported in the remaining patient [
13]. In a prospective
study of conversion from CsA to sirolimus in 15 renal transplant
recipients, Stallone
et al. [
5] showed that all KS lesions underwent
complete regression within 3 months. Continuing remission from
KS was confirmed by histological examination 6 months after
conversion, and no episodes of acute rejection or changes in
renal graft function were reported in any of the patients. Immunohistochemical
analysis of the lesions from these patients showed a significant
increase in components of the angiogenesis-signalling pathways
known to be disrupted by the PSIs, compared with normal skin
from the same patients (
Figure 1) [
5]. Recently, regression
of visceral KS after conversion to sirolimus has also been reported,
with complete regression of visceral and cutaneous lesions occurring
in a transplant recipient within a few months of conversion
[
14]. In accordance with these data, abrupt onset of KS was
reported in a renal transplant recipient following the withdrawal
of sirolimus [
15]. Recent studies have suggested a possible
mechanism for the action of PSIs on preventing angiogenesis
in tumours [
5]. Animal models have demonstrated that PSI activity
impairs VEGF production and limits the response of endothelial
cells to VEGF stimulation, therefore inhibiting tumour progression
[
16]. Furthermore, a recent study demonstrated that Kaposi's
sarcomagenesis involves stimulation of tuberin phosphorylation
by vGPCR and activation of mammalian target of rapamycin (mTOR)
through both direct and paracrine mechanisms [
17]. Inhibition
of mTOR with sirolimus prevented vGPCR sarcomagenesis, highlighting
a potential role for mTOR in the initiation of KS.
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Fig. 1. Expression of the angiogenesis-related signalling proteins (A) vascular endothelial growth factor and (B) foetal liver kinase-1/kinase domain receptor is significantly increased in Kaposi's sarcoma lesions compared with normal skin [5] (Reprinted with permission from Massachusetts Medical Society). VEGF, vascular endothelial growth factor; Flk-1/KDR, foetal liver kinase-1/kinase domain receptor.
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To gain a better understanding on how conversion to a PSI can
improve post-transplant outcomes relating to KS, previously
unpublished patient data from transplant physicians in multiple
centres across Europe and Australia have been pooled to provide
a more extensive patient population for analysis and treatment
guidance (
Table 2). This analysis only included renal transplant
recipients who were converted to PSIs following the development
of KS. Twelve renal transplantation recipients identified from
six different transplant centres were converted to PSIs (everolimus,
n = 4; sirolimus,
n = 5).The range of PSI blood levels was 3–9
ng/ml in patients receiving everolimus and 5–12 ng/ml
in patients receiving sirolimus; CNIs were withdrawn in all
patients. Following conversion, resolution of lesions was observed
in 11 patients, with stable renal function and no episodes of
acute rejection reported. In one patient, the introduction of
a PSI along with CsA withdrawal did not lead to resolution of
KS and chemotherapy was introduced. This patient also experienced
proteinuria and pneumocystosis following conversion. Conversion
to PSIs was generally well tolerated in all patients with only
one patient experiencing adverse events (skin disorders and
hyperlipidaemia).
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Table 2. Clinical experience of proliferation signal inhibitors in post-transplantation Kaposi's sarcoma from six European and Australian Transplant centres
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Summary
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KS is a common long-term complication in renal transplant recipients,
with an increased incidence compared with the general population,
and being especially prevalent in Mediterranean and African
populations. There is increasing clinical data suggesting that
conversion to PSIs in patients with KS causes regression of
lesions through effects on VEGF signalling. This immunosuppressive
regimen may, therefore, reduce the impact of KS on the long-term
outcomes of kidney transplantation.
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Acknowledgements
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Data on KS was collected from the following centres:
Westmead Hospital, Westmead, Australia; Hôpital Hotel Dieu, CHU de Nantes, Service du Pr Soulillou, Nantes, France; Cologne General Hospital, Merheim Medical Center, Germany; Universitätsklinikum Charite, Abeteilung fur Nephrologie, Berlin, Germany; Department of Nephrology and Transplantation, Laiko Hospital, Athens, Greece; Renal Unit, Department of Nephrology, Hospital Clínic, University of Barcelona, Spain
Editorial assistance was provided by Ogilvy 4D.
Conflict of interest statement. Dr J.M.C. received an honorarium from Novartis Pharma AG for participation in the workshop in Rome, March 2006, on the role of everolimus in the management of post-transplant malignancies in renal transplantation.
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Abstract
Introduction