disorder in pediatric kidney-transplant
recipients – A national study
KT has greatly improved the life expectancy and
quality of life of patients with ESRD. However,
although the increasingly potent immunosup-
pressive drugs significantly prolong graft and
patient survival, they expose patients to an
increased risk of infections and neoplasia (1–4).
According to the NAPRTCS report of 2010
(5), malignancy rates among pediatric kidney-
transplant recipients are currently 2.4%. The
Cleper R, Ben Shalom E, Landau D, Weissman I, Krause I, Konen O,
Rahamimov R, Mor E, Bar-Nathan N, Frishberg Y, Davidovits M.
Post-transplantation lymphoproliferative disorder in pediatric kidney-
transplant recipients – A national study.
Abstract: PTLD is the most common malignancy in pediatric kidney-
transplant recipients. We examined the prevalence, clinical features, and
outcome of PTLD in Israel. Twelve (4.4%) of 272 pediatric (<19 yr)
kidney-transplant recipients retrieved from a search of the NIKTR for
1991–2008 had acquired PTLD at a median of 3.2 yr post-transplan-
tation. PTLD-affected patients were younger at transplantation (4.2 vs.
12.5 yr, p = 0.02), had a higher rate of OKT3 therapy for acute
rejection (25% vs. 4%, p = 0.015), and 5/12 were EBV-seropositive at
transplantation. Graft dysfunction was the presenting sign in six (50%).
PTLD was predominantly abdominal (83%) and B-cell type (67%);
T-cell PTLD occurred exclusively in EBV-seropositive patients.
Treatment consisted of immunosuppression cessation (6/12, 50%),
antiviral agents (7/12, 58%), anti-CD20 monoclonal antibodies (4/12,
33%), and chemotherapy (6/12, 50%). Survival was 100% in the
EBV-naı¨ve patients and 40% in the EBV-seropositive patients. Graft
loss occurred in three of eight survivors (37.5%). PTLD-associated
mortality risk was older age: 11.2 vs. 3.4 yr, longer dialysis: 15 vs.
6.5 months, T-cell type disease (75%), later PTLD onset: 6.35 vs. 1.9 yr
post-transplantation and era of transplantation (43% mortality before
vs. 20% after 2001). Pretransplantation EBV-seronegative status might
confer a survival benefit with early detected PTLD. EBV-seropositive
patients are at risk for aggressive late-onset lethal PTLD.
Roxana Cleper1,2,3, Efrat Ben
Shalom4,5, Daniel Landau6,7, Irith
Weissman8, Irit Krause1,2, Osnat
Konen2,9, Ruth Rahamimov2,10, Eytan
Mor2,10, Nathan Bar-Nathan2,10,
Yaakov Frishberg4,5and Miriam
1Institute of Nephrology, Schneider Children?s
Medical Center of Israel, Petach Tikva, Israel,
2Sackler Faculty of Medicine, Tel Aviv University, Tel
Aviv, Israel,3Pediatric Nephrology Service, Dana-
Dwek Children?s Hospital, Tel Aviv Souraski Medical
Center, Tel Aviv, Israel,4Division of Pediatric
Nephrology, Shaare Zedek Medical Center,
Jerusalem, Israel,5Hadassah-Hebrew University
School of Medicine, Jerusalem, Israel,6Department
of Pediatrics A and Pediatric Nephrology Clinic,
Soroka Medical Center, Beer Sheva, Israel,
7BenGurion University of the Negev, Beer Sheva,
Israel,8Department of Pediatric Nephrology and
Dialysis, Western Galilee Hospital, Nahariya, Israel,
9Department of Pediatric Radiology, Schneider
Children?s Medical Center of Israel, Petach Tikva,
Israel,10Department of Transplantation, Rabin
Medical Center, Beilinson Hospital, Petach Tikva,
Key words: EBV – kidney transplantation – outcome
– pediatric – post-transplantation lymphoproliferative
Roxana Cleper, MD, Institute of Pediatric Nephrology,
Schneider Children?s Medical Center of Israel, Petach
Tikva 49202, Israel and Pediatric Nephrology Service,
Dana Dwek Children?s Hospital, Tel Aviv Souraski
Medical Center, Tel Aviv 64239, Israel
Tel.: +972 3 6972512
Fax: +972 3 6972411
Accepted for publication 24 April 2012
Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr
virus; ESRD, end-stage renal disease; GH, growth hor-
mone; rGH, received growth hormone; IMN, infectious
mononucleosis; IVIG, intravenous immunoglobulins; KT,
Pediatric Renal Transplant Cooperative Study; NIKTR,
National Israeli Kidney Transplant Registry; PCR, poly-
merase chain reaction; PTLD, post-transplantation lym-
Pediatr Transplantation 2012
? 2012 John Wiley & Sons A/S.
rates for adults are lower: 0.45–1.4% according
to the Scientific Registry of Transplant Recipi-
ents and the US Renal Data System (6–8). PTLD
accounts for 80% of the post-transplant child-
hood malignancies, probably owing to the great-
er extent of lymphoid tissue in this population,
whereas skin cancer is the most common type of
malignancy in adult kidney recipients (3, 4).
PTLD is a heterogenous group of diseases
characterized by the uncontrolled proliferation
of lymphoid cells following immunosuppression
for solid organ and hematopoietic cell transplan-
tation. The spectrum of PTLD ranges from
lymphoid hyperplasia and IMN-like disease to
highly malignant lymphoma (9). The risk varies
by the intensity and duration of immunosup-
pressive therapy (6–8, 10), and it is 30- to 70-fold
higher in patients with a negative EBV serostatus
before transplantation (4, 10, 11). Geographic,
race-related and genetic factors also seem to play
a role (9, 12, 13). The aim of this study was to
describe the prevalence, clinical features, risk
factors, and outcome of PTLD in pediatric KT
recipients in Israel.
Materials and methods
Since the 1990s, all kidney transplants performed in Israel
have been documented and followed in the NIKTR, under
the directorship of the Department of Transplantation,
Rabin Medical Center. For this study, the registry database
was searched for all pediatric (age <19 yr) KT recipients
diagnosed with PTLD from 1991 to 2008 and followed at
one of the six pediatric nephrology units in Israel (usually to
age 25). In addition, we searched the databases of these
units for patients who had undergone transplantation
abroad during the same period. Patients after combined li-
ver-KT and patients with a functioning graft less than three
months after transplantation were excluded. The patients
diagnosed with PTLD after transplantation were identified
and formed the study group. Their findings were compared
with the remaining patients, without PTLD. The diagnosis
of PTLD was based on predefined criteria (9).
The post-transplant maintenance immunosuppression
protocol used after transplantation was modified over the
study years as follows:
1991–1996: prednisone, azathioprine, and cyclosporine A
1997–2001: prednisone, tacrolimus, and azathioprine
Since 2001: prednisone, tacrolimus, and mofetil myco-
Changes in induction therapy were as follows:
1991–2002- antithymocyte globulin, two to seven doses
Since 2006- two doses of daclizumab- one preoperatively
and one on day 14 according to the TWIST Study protocol
For prophylaxis, acyclovir for six months was standard
until 2000; thereafter, it was replaced by valgancyclovir
prophylaxis for three months until 2004 and extended later
on (after 2004) to six months, depending on the pre-trans-
plantation CMV status.
In patients diagnosed with PTLD, immunosuppression
was modified according to the tumor stage: reduced for
‘‘early’’ and polymorphic types and terminated completely
for monomorphic PTLD. The therapeutic protocol for
PTLD was not uniform because the patients were treated
at different medical centers during different periods of
For this study, the following data were collected for each
patient: cause of ESRD, type and duration of renal
replacement therapy and GH therapy prior to transplan-
tation, pre-transplantation CMV and EBV serology, age at
transplantation, donor type, induction therapy and main-
tenance immunosuppressive protocol, acute rejection epi-
sodes (during first post-transplantation year) and therapy,
type of antiviral prophylaxis (when applicable), episodes of
primary CMV infection, time from transplantation to
diagnosis of PTLD, PTLD diagnostic procedure, site of
occurrence of PTLD, histopathological diagnosis and
staging, findings for plasma EBV DNA PCR at PTLD
diagnosis (if applicable), therapy for PTLD, and outcome.
Pre- and post-transplantation clinical and laboratory find-
ings were compared between patients with and without a
diagnosis of PTLD. However, pre-transplant EBV sero-
status was not recorded routinely in the registry and was
not available for the whole transplant population, and
EBV PCR surveillance was instituted only in 2006. In
addition, data were not available on EBV serology findings
in the kidney donors.
Data were analyzed with Pearson?s chi-square test, Fisher
exact t-test, or Mann–Whitney test, as appropriate.
We retrieved the medical data of 300 patients,
112 female (37.3%) and 188 male, who received a
total of 327 kidney grafts, including 299 trans-
planted in Israel, from 1991 to 2008. Twenty-
eight patients were subsequently excluded from
the study, according to the predefined criteria.
The remaining 272 patients (170 male) were
followed for a median duration of 5.9 yr (range:
three months to 17 yr).
PTLD was diagnosed in 12 of the 272 patients,
for a prevalence of 4.4%. The incidence density
rate for PTLD was 747/100 000 post-transplan-
tation years (CI 624:837). Seven patients were
men and five women; all were Caucasian. Age at
transplantation ranged from two to 18 yr (med-
ian 4.2 yr, mean 7.03 ± 5.76 yr); seven patients
were younger than five yr at transplantation. All
were first-time KT recipients at the time of
diagnosis of PTLD.
The demographic and clinical data of study
group are detailed in Table 1. Half (six) of the
patients diagnosed with PTLD were EBV-naı¨ve
at transplantation while five were EBV-seropos-
Cleper et al.
itive and in one patient, and the EBV status was
unknown. Six of the patients with PTLD had
rGH therapy during their CKD course; six of
them had received a living-donor graft, and three
had been transplanted preemptively. Three pa-
tients (25%) had acute rejection episodes that
were treated with high-dose methylprednisolone
in combination (in two cases) with antithymocyte
globulin or OKT3.
By comparison to their non-affected counter-
parts, patients with PTLD were significantly
younger at transplantation (p = 0.002) and had
more often OKT3 therapy for acute rejection
(p = 0.015) (Table 2). Of note, all the recorded
acute rejection episodes occurred during the first
year after transplantation. The duration of pre-
transplant dialysis and CMV serology were
similar in the two groups. As noted, the groups
could not be compared for pre-transplant EBV
serology because of missing data for the major-
ity of patients in the registry. Pre-transplanta-
tion rGH therapy data were available for a small
part of the registry population – 40 patients – of
these 25% (10 pts) had received this therapy
(data not shown). The rate of living-donor grafts
was lower in the patients without PTLD: 38%
vs. 50%, but the difference was not statistically
significant. This was also true for use of induc-
Data are shown in Table 3.
PTLD was diagnosed at a median of 3.25 yr after
transplantation (range: 0.5–15.5 yr). Half the
cases were diagnosed within five yr after trans-
plantation, including three (25%), during the first
post-transplantation year. Seven patients with
PTLD underwent transplantation in 1991–2000
(4.8% of all pediatric kidney-transplant recipients
during this period) and five, in 2001–2008 (3.9%
of all the pediatric kidney-transplant recipients).
The most common presenting symptoms of
PTLD were fever in eight of 12 patients with
PTLD, graft dysfunction (diagnosed by routine
blood tests) six of 12, and abdominal complaints
(including gastrointestinal bleeding) six of 12. In
four of the febrile patients, other findings
included lymphadenopathy and hepatospleno-
megaly, constituting an IMN-like syndrome. The
graft dysfunction resolved spontaneously (prior
Table 1. Demographic characteristics of study population: patients with post-
No. of patients, n (males/females)
Underlying disease, n
Age at KT (yr), median (range)
Pre-KT GH therapy, n
Preemptive KT, n
EBV-negative serology at KT, n
Use of antilymphocytic agents:
Immunosuppressive therapy, n§
*Including four patients with focal segmental glomerulosclerosis and one
patient with diffuse mesangial sclerosis (Denys-Drash syndrome).
?ATG and anti-IL2 Abs – for induction; OKT3 – for rejection.
§All 12 patients received corticosteroids as part of immunosuppressive pro-
Table 2. Comparison of background and transplantation-related data in pa-
tients with and without PTLD
With PTLD Without PTLDp value
Total No. of pts. (% male)
Age at KT (yr),
Age at KT (yr),
mean € s.d.
Duration of pre-
transplant RRT (mos),
serostatus at KT
therapy, n (%)
Acute rejection during
first post-KT year
7.03 € 5.76 11.67 € 5.010.002
5 (42) 158 (61) 0.23
3 (25)70 (27)1
11 (92)/1 (8)
6 (50)/4 (33)
182 (70)/78 (30)
3 (25) 42 (16)0.01
RRT, renal replacement therapy; NA, not available; AZA, azathioprine; MMF,
PTLD in pediatric kidney transplantation
to any intervention) in four of the six affected
patients. One patient presented with limping
because of tumor pressure over the nerve roots.
In four of the six EBV-naı¨ve patients, increas-
ing titers of plasma EBV DNA on PCR during
routine monitoring raised the first suspicion of a
malignancy (data not shown). The diagnosis was
confirmed by ultrasound in eight patients and
computerized tomography or positron emission
tomography in four.
The most common site of PTLD was the
abdomen, in 10 patients (83%) with nodal
involvement (including retroperitoneal lymph-
adenopathy with/without splenomegaly) in six
and extranodal involvement in four: two para-
spinal mass, one gastric lymphoma diagnosed on
gastroscopy, and one kidney-graft involvement.
Of the remainder, one patient had a palatal
Table 3. Clinical, histopathological and outcome features of PTLD in pediatric kidney transplant recipients- 1991–2008
KT to PTLD
1 9.2F+ 1991 15.5 (2006) Abdominal pain,
Ly n + spleen
mesenteric Ly n
Tc anaplastic, CD20-,
NA gastric tumor
EBV- abdominal Ly
CD20+, EBV- NA
Stop: CyA +
2 18F NA1995 5 (2000) Fever, abdominal
Tacfl, stop AZA,
3 13.3M+ 1997 7.7 (2001)Fever,
CyAfl, stop AZA,
4 4.5M+ 19981.2 (1999)
Stop Tac (not on MMF)
5 16M+ 1998 0.9 (1999)IMN-like
Stop Tac + AZA CHOP, IVIG,
a INF, ganciclovir
lost at 1 yr
6 2.5F+ 19984.5 (2002) Abdominal pain,
Stop Tac + AZA
6.5Alive GFR =
77M)19994 (2003)Fever, malaise,
Stop Tac (not on MMF)
5.7Alive, graft lost
1 yr post PTLD
83F)2001 0.5 (2001)Fever,
Stop Tac + MMF,
Stop Tac, MMFfl,
7 Alive GFR =
B cell polymorphic,
CD20+, EBV? Oral:
''Early lesion,'' EBV+
cervical Ly n,
''Early lesion,'' EBV+
mesenteric Ly n +
''Early lesion,'' EBV+
CD20+ abdominal +
retroperitoneal Ly n,
1.9Alive GFR =
103.5M)2003 2.5 (2005)Recurrent fever,
Tacfl, stop MMF,
4Alive GFR =
112F)20051.1 (2006) IMN-like, OSA,
Stop Tac, MMFfl,
2.9Alive GFR =
123M)2005 1.3 (2006)IMN-like,
Tacfl, stop AZA,
2.5Alive GFR =
AZA, azathioprine; CHOP, cyclophosphamide, vincristine, daunorubicine, prednisone; CyA, cyclosporine A; GFR, glomerular filtration rate; GFRfl, depressed kidney
graft function; GI, gastrointestinal; Mini CHOP, low-dose cyclophosphamide + dexamethasone; MMF, mofetil mycophenolate; Tac, tacrolimus; Ly n, Lymph nodes
(enlarged);8CD20, EBV, Refer to tumor staining for CD20 positive B cells and EBV; EBV, Epstein Barr virus, NA, not available.
Cleper et al.
tumor and one cervical lymphadenopathy. There
were no cases of primary central nervous system
or bone marrow involvement. All patients under-
went bone marrow biopsy at PTLD diagnosis.
Eight tumors (67%) were B-cell type, of these
three were considered ‘‘early’’ type with poly-
clonal B-cell predominance. All B-cell tumors
were diagnosed until the third year after KT.
Three patients had T-cell type PTLD, which
occurred late in all cases (five to 15.5 yr after
KT). The remaining patient was initially diag-
nosed with polymorphic-type PTLD but was
later found, on a post-splenectomy pathological
examination, to have visceral human herpesvirus
8-associated Kaposi sarcoma. This case has been
reported previously (15). In two patients with T-
cell PTLD, secondary central nervous system
dissemination was diagnosed during relapse or
EBV staining was positive in only three of the
eight B-cell type PTLD, negative in all the T-cell
type PTLD and in the Kaposi-type lymphoma
and unavailable data in two of eight cases. CD20
staining was positive in five of eight of the B-cell
type PTLD and unavailable for the other three
Immunosuppression was reduced in six patients
with PTLD and completely stopped in the
remainder. Seven patients were treated with
antiviral therapy (acyclovir or ganciclovir), and
three with CMV hyperimmune globulin or IVIG.
Four of the six patients in whom immunosup-
pression was stopped also received anti-CD20
administered to six patients, and complementary
surgery was performed in five (data not shown in
Table 3). One patient with brain metastases/
sagittal vein thrombosis received radiotherapy.
Eight of the 12 patients with PTLD were still alive
at a median post-remission follow-up time of four
yr (range 1.9 to nine yr), for an overall survival
rate of 67%. One of the survivors had B-cell type
palatal PTLD that recurred within 15 months of
diagnosis and responded to significant immuno-
suppression reduction; he has been in remission
for 19 months. All deaths (33% of patients)
occurred within 0.4–1.5 yr after PTLD diagnosis.
Graft function was preserved in five of the
eight survivors(62.5%). Amongthe three
patients who lost graft function, in two this
happened during the first year post-PTLD diag-
nosis. One of these patients has undergone
PTLD recurrence for almost two yr follow-up.
The other two are still receiving renal replace-
Prognostic factors in patients diagnosed with PTLD
The following factors were associated with poor
survival (trend level) after diagnosis of PTLD:
EBV-seropositive status before transplantation,
longer dialysis period before transplantation,
older age at KT, receipt of a cadaveric donor
graft, and later onset of malignancy after trans-
plantation (Table 4). Some of these factors tend
to co-associate with each other; however, multi-
variate analysis was considered inappropriate
because of the small sample size.
PTLD type had a significant impact on
outcome as of the four patients who died, three
had T-cell PTLD, diagnosed at a median of
7.7 yr after transplantation, and one had large
gastric B-cell lymphoma, diagnosed in the second
year after transplantation. Of note, three of the
five patients who were EBV-seropositive before
transplantation had non-B-cell type PTLD.
The time within the study period when trans-
plantation was performed may also have affected
outcome: from 1991 to 2001, the mortality rate
was 43% (three of seven patients with PTLD);
thereafter (to 2008) it dropped to 20% (one of
five patients with PTLD) (Table 3).
EBV-naı¨ve patients developed PTLD earlier
post-transplantation (1.9 yr vs. 6.3 yr) and had
exclusively B-cell type PTLD (Table 4). Most
significantly, none of these patients died with
PTLD as opposed to 60% of the EBV-seropos-
itive patients at transplantation.
Table 4. Outcome of PTLD by patient characteristics
Age at KT (yr),
Duration of RRT (mos),
transplant, n (%)
Time KT to PTLD (yr),
T-cell type PTLD,
11.2 (4.9–18)3.4 (2–16)
15 (10–36) 6.5 (0–24)
1 (25%)5 (62.5%)
6.35 (1–15.5)1.9 (0.5–4.7)
PTLD in pediatric kidney transplantation
This study sought to determine the characteristics
and profile of PTLD in children and adolescents
long-term threat for successful KT. We calculated
a 4.4% rate of PTLD nationwide or an incidence
density rate of 747/100 000 post-transplantation
years in our pediatric kidney-transplant popula-
tion. These values are higher than the 298–395/
100 000 post-transplantation years rate reported
in the NAPRTCS for 1987–1996 (16) and also the
2.3% incidence documented in the more recent
NAPRTCS Report 2010 (5). However, we found
that the rate of PTLD progressively decreased
our study period.
Our high rate of PTLD compared to earlier
studies may be explained by the use of induction
protocols including antilymphocytic agents and
the high rate of OKT3 use for acute rejection
episodes, which are associated with a 1.8–4.7-fold
higher risk of PTLD than other protocols (6, 7,
10, 14, 17, 18). OKT3 has since been abandoned
by our transplantation center and most others. It
is noteworthy that the most recently imple-
mented protocol in Israel consists of anti-IL-2
antibodies, which has also been linked to PTLD
risk in some studies (6) but not others (7, 17). In
addition, the relatively high rate of living-donor
grafts in our PTLD group (50% vs. 36% for the
transplant recipients without PTLD), with pos-
sibly higher expectations for graft outcome,
might have prompted physicians to increase the
intensity of immunosuppression to prevent rejec-
tion. Finally, the longer follow-up period in our
population – median 5.9 yr – with a higher
exposure might have also contributed to the
observed increased PTLD rate. Earlier large-
scale studies found no clear-cut correlation
between PTLD risk and type of calcineurin
inhibitor used (19) as also found in our data.
GH therapy during the pre-transplantation
period was reported to increase the post-KT
PTLD risk for those transplanted at an early age
(20). The NIKTR contains very limited data on
rGH treatment, precluding our analysis of this
factor. Nevertheless, it is noteworthy that half of
our patients in whom PTLD developed had been
treated with rGH during the pre-transplantation
Primary EBV infection in kidney-transplant
recipients is usually acquired by EBV-naı¨ve
patients through grafts from EBV-positive do-
nors or later, by community exposure. EBV
infection serves as the trigger of pediatric PTLD
in 90% of cases (10, 11), and it is considered the
most important cause of PTLD in this age group,
with an estimated risk of 14–24% (4, 14).
Although the EBV serology status before trans-
plantation was missing from the NIKTR, about
half the patients with PTLD were EBV-seropos-
itive at transplantation, pointing to a lack of
protection from PTLD in this subpopulation.
Similar findings were reported for liver-graft
recipients with EBV reactivation, which was
found to be the cause of PTLD in 25% of cases
(21). By contrast to other reports (4, 11), in this
study, CMV infection did not play a major role
in PTLD occurrence.
The median time to PTLD diagnosis was
3.25 yr (1.9 yr for EBV-naı¨ve patients), which is
considerably longer than the reported 0.5–1.5 yr
(5, 10, 12, 14). The long lag may be related to the
antiviral therapy given during the first three to
six months, mainly for CMV prophylaxis in
CMV-naı¨ve recipients. Antiviral use was also
reported to lower PTLD rate (10, 22).
Fever, either alone or as part of IMN-like
syndrome, is a widely reported symptom of
PTLD (4, 11, 12) and was observed in 66% of
our cases. In addition, six patients had graft
dysfunction at presentation, which has not been
reported in the past.
The predominantly abdominal localization of
PTLD, observed in 83% of our cases, is well
recognized and may be attributable to the
continuing allogeneic stimulation of the host
immune system by the allograft (2, 11–13, 23,
24). However, in only one case did we find
primary graft involvement by PTLD, whereas
most other series had rates of 11–32% (11, 25,
26). Our high rate of nodal involvement is similar
to previous series of pediatric kidney-transplant
recipients with PTLD (3, 4, 12), but contrasts
with the 68% rate of extranodal tumors in adult
PTLD (2, 24, 25). As in recent reports, none of
our patients had primary central nervous system
or bone marrow involvement by contrast to
earlier reported rates of 20–30% (3, 21, 24–27).
Most of the tumors were B-cell type, as usually
in 25% of the study group, exclusively in patients
who were EBV-seropositive at transplantation.
There are only 16 reports in the literature of T-cell
PTLD in the pediatric age group (28, 29). In
agreement with these reports, our cases of T-cell
PTLD all occurred late (five to 15 yr after KT),
and all these patients died of the disease.
The case of Kaposi-type PTLD is also very
unusual (15). The reported rate of this complica-
Cleper et al.
tion in renal transplant recipients is only 0.2–5%,
with an increased propensity in endemic popula-
tions(30). Like in ourpatient, Kaposi-typePTLD
occurs early after transplantation and rarely
evolves into malignant lymphoma (4.5%); when
it does, the prognosis is dire (30). We decided to
include this case in our series despite Kaposi
sarcoma being considered a different malignancy
type, because the final pathological diagnosis
(based on immunohistochemistry and PCR stud-
ies of one of the lymph node biopsies performed
during the disease course) was HHV-8 induced
polymorphic-type PTLD and Kaposi sarcoma (a
recognized HHV-8-driven tumor type).
Reduction of immunosuppression is a report-
edly efficient management modality in 66% of
PTLD cases (25), although chemotherapy is
required in about half of them. Need for chemo-
therapy was reported to associate with reduced
survival rate in adults with PTLD: <50% two-yr
survival (31). In our series, as well, three of six
patients treated with chemotherapy died of the
disease. Of note, other pediatric series report a
much better outcome of chemotherapy-treated
PTLD (32, 33).
Overall mortality in the present series was 33%
with all deaths occurring within 0.4–1.5 yr post-
PTLD diagnosis. This rate is comparable to
other reports (4, 11, 13, 25, 27) but higher than
more recent series: 0–13% (5, 26, 32, 34). These
results might be explained by changes along the
17 yr period covered by this study in the aware-
ness and diagnostic methods for PTLD monitor-
ing and management.
Good prognostic factors in our study were
EBV-seronegative status at transplantation and
acute rejection episodes, while a poor prognosis
was associated with longer duration of dialysis,
and olderage at PTLD diagnosis, as reported also
elsewhere (7, 25, 35). Furthermore, the high
mortality reported by others for early-onset
in all cases of death, PTLD was diagnosed at a
median of 6.35 yr after KT. A similar finding was
reported in liver-transplant recipients (21).
For survivors of PTLD, a 38% graft loss rate
during a median follow-up period of four yr was
found, which is comparable with other reports
(35), although one study found only a 12% rate
(26). As expected, the patients with graft loss
were either those with disseminated disease or the
one with graft involvement by the tumor.
as reflected in the variety of immunosuppressive
viral infection monitoring and management.
revealed a shift toward increased awareness of
themedicalteamofthe diagnosisof PTLD, which
led to improved outcome, as highlighted by the
lack of PTLD-associated mortality in patients
who underwent transplantation after 2000 and
lack of new early-onset cases during the last three
yr of the study period.
Despite the above-stated drawbacks, several
conclusions can be reached from our study:
1 Graft dysfunction is a possible important pre-
senting sign of PTLD along with well-known
but nonspecific symptoms of abdominal pain
2 EBV-naı¨ve patients are at highest risk for tu-
mor development during the first three to four
yr after KT. Their prognosis may be improved
with proper monitoring and early diagnosed.
3 EBV-seropositive patients at KT have worse
chances for survival when diagnosed with late-
onset PTLD, which are usually highly malig-
4 The high rate of abdominal PTLD tumors
underscores the importance of early ultra-
sound examination and routine surveillance.
5 Persistent high-grade vigilance and close mon-
itoring to prevent overimmunosuppression in
the long-term after KT are crucial for early
diagnosis and successful therapy and survival
of late-onset PTLD.
Conflict of Interest
None to declare.
R. Cleper: involved in concept/design, data col-
lection, data analysis/interpretation, statistics,
drafting the manuscript, and critical revision of
the manuscript; E. Ben Shalom: involved in data
collection, data analysis/interpretation. D. Lan-
dau: involved in concept/design, data analysis/
interpretation, critical revision of the manuscript.
I. Weissman: involved in data collection, data
analysis/interpretation. I. Krause: involved in
data analysis/interpretation, critical revision of
the manuscript. O. Konen: involved in data
collection, data analysis/interpretation. R. Rah-
amimov: involved in data collection, data analy-
sis/interpretation. E. Mor: involved in design/
sion of the article. N. Bar Nathan: involved in
design/concept, data analysis/interpretation. Y.
Frishberg: involved in concept/design, data anal-
ysis/interpretation. M. Davidovits: involved in
PTLD in pediatric kidney transplantation
concept/design, data analysis/interpretation, and Download full-text
critical revision of the article.
The authors wish to thank Maya Mor, Coordinator of the
National Israeli Kidney Transplantation Registry, for her
help with data retrieval and statistical analysis, and Pnina
Lilos, Statistician, for her help with data analysis.
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