Pediatr Blood Cancer 2007;48:500–503
Renin-Induced Hypertension in Wilms Tumor Patients
M.H. Maas, MD,1 K. Cransberg, MD,2 M. van Grotel, MD,1
R. Pieters, MD, PhD,1 and M.M. van den Heuvel-Eibrink, MD, PhD1*
Background. Since the report that hypertension associated with
Wilms tumor (WT) may be renin-induced, no larger series than 13
patients have been published. Nevertheless, angiotensin converting
enzyme (ACE) inhibitors have become treatment of choice for
hypertension in WT patients. The purpose of this study was to
investigate the correlation between plasma renin levels and blood
pressure in a larger cohort of WT patients. Procedure. In this
retrospective, single-center study, data on blood pressure and plasma
renin were analyzed in 86 WT patients treated according to the
consecutive SIOP protocols 6, 9, 93-01, and 2001. Results. At
diagnosis, 47 WT patients suffered from hypertension (55%). In 31 of
these patients plasma renin levels were analyzed; increased plasma
Key words: hypertension; nephroblastoma; renin
INTRODUCTION
At presentation children with nephroblastoma can show
hypertension. The correlation of Wilms tumor (WT) with elevated
blood pressure was first described in 1937 by Bradley [1]. The first
correlation between elevated plasma renin levels and elevated blood
pressure in WT patients was reported in 1969 by Spergel et al. [2].
They described one patient with WT and severe hypertension and
showed that renin was secreted by the tumor. Since then, more
reports have confirmed hyperreninaemia in children with WT but no
larger series than 13 WT patients are available [3,4]. Nevertheless,
this correlation is the rationale for using angiotensin converting
enzyme (ACE) blockers as therapy for hypertension in WT patients
soon after they became available in 1979. The renin-angiotensin
system plays a major role in the control of blood pressure. Following
renin production in the kidney, angiotensinogen is converted to
angiotensin I, which is subsequently converted to angiotensin II by
ACE. Angiotensin II production results in vasoconstriction,
followed by hypertension. If hypertension in WT patients is renin-
mediated, an ACE inhibitor would be the most effective anti-
hypertensive drug [5]. This study was performed to evaluate the
occurrence of hypertension in WT patients, and the correlation
between renin production and hypertension, in a single-center
cohort of WT patients.
METHODS
Patients
From 1982 to 2003, in our hospital 86 children were diagnosed
with WT. This cohort (median age at diagnosis 3.0 years (range 0–
12 years)), included 44 patients with stage I, 15 with stage II (staging
according to SIOP 93-01: 14 without positive lymph nodes and 1
with positive lymph nodes), 17 with stage III, and 10 with stage IV
patients at diagnosis [6]. All patients were treated with 4 to 8-week
preoperative chemotherapy, followed by surgery and postoperative
chemotherapy and/or radiotherapy according to the consecutive
SIOP WT protocols 6 (n ¼ 17), 9 (n ¼ 35), 93-01 (n ¼ 23), and 2001
(n ¼ 11) [6,7]. Of the 86 children, 11 eventually suffered from a
relapse. The 3-year event free survival (EFS) was 87% and the
overall survival (OS) was 90%. Informed consent was obtained from
ß 2006 Wiley-Liss, Inc.
DOI 10.1002/pbc.20938
renin levels were found in 25/31 patients (81%). In contrast, normal
plasma renin levels were measured in 8/13 of the patients with a
normal blood pressure (P ¼ 0.012). Twenty-eight children received
antihypertensive treatment before surgery, in 25 of them blood
pressure normalized before surgery. Blood pressure was normal
directly after surgery in all patients but 4, in whom blood pressure
recovered to normal within a few weeks. Conclusions. This
retrospective study shows that hypertension in WT patients is
associated with elevated plasma renin levels, indicating that ACE
inhibitors may be a good therapeutic option in at least a subset of WT
patients with hypertension before nephrectomy. Pediatr Blood
Cancer 2007;48:500–503. ß 2006 Wiley-Liss, Inc.
all patients and parents according to the declaration of Helsinki,
after approval of the institutional ethical committee.
Methods
For this retrospective study, clinical information was obtained
from the medical records, at presentation, during treatment and after
completion of therapy. Information on histology subtypes, as well as
clinical data on blood pressure values at presentation, before and
after surgery, and on the used antihypertensive treatment regimen
were collected. Blastemal predominance (BP) was defined as >66%
blastema of the remaining tumor after presurgery chemotherapy in
patients with <66% necrosis (Bergeron et al., abstract O131, SIOP
meeting 2003). The group of blastema-containing patients consisted
of the BP group together with all other patients with a blastema-
containing tumor.
Hypertension was defined as an average systolic and/or diastolic
blood pressure
95th percentile for age and gender, with
consecutive measurements obtained on at least three occasions,
using international guidelines for children [8]. From the start of the
study blood pressure was measured electronically using Dinamap
(GE Healthcare, Critikon, Tampa, FL). The decision to take blood
samples for renin levels at the time of diagnosis was based on the
choice of individual doctors, as part of the diagnostic work-up. In
most cases chemotherapy was started within 48 hr of diagnosis, after
radiological confirmation of renal tumor, staging and obtaining the
negative result of VMA screening. If hypertension occurred,
reported within the first 3 days after the diagnostic work-up, the
patient was considered hypertensive.
Plasma renin levels at diagnosis were measured by a radio-
immunoassay method, using specific monoclonal antibody for renin
(Nichols institute Diagnostics, San Clemente, CA). The reference
— —————
1
Department of Pediatric Oncology/Hematology, Erasmus MC, Sophia
Children’s Hospital, Rotterdam, The Netherlands; 2Department of
Pediatric Nephrology, Erasmus MC, Sophia Children’s Hospital,
Rotterdam, The Netherlands
*Correspondence to: M.M. van den Heuvel-Eibrink, Erasmus MC,
Sophia Children’s Hospital, Room Sp 2568, P.O. box 2060, 3000 CB
Rotterdam, The Netherlands. E-mail: m.vandenheuvel@erasmusmc.nl
Received 1 January 2006; Accepted 16 May 2006
 Renin-Induced Hypertension in Nephroblastoma 501

range for renin according to age, has been assessed in our hospital by
Fiselier [8,9]. The measured renin values are indicated as Z-scores.
The Z-scores of the hypertensive patients are depicted in Table I.
Increased renin was defined by Z-scores above 1.
Statistical Analysis
All data were analyzed using SPSS software. Differences in
parameters were tested with Chi-square test for categorical variables
and with t-test for continuous variables. All reported P-values are
two-sided and a significance level of a ¼ 0.05 was used.
RESULTS
Of the 86 WT patients (50 boys and 36 girls), 47 (55%) presented
with hypertension (Table I). In 44 patients (31 hypertensive and
13 normotensive) plasma renin concentrations were measured.
Elevated renin levels were found in 25/31 hypertensive patients

TABLE I. Wilms Tumor Patients With Hypertension

Patient SIOP protocol Gender Age (months) Stage Histology Tumor volume (ml) Renin levels (Z-score)

1 1 M 36 I MC 580 0.9
2 93-01 M 11 III MC 540 0.7
3 9 M 138 II MC 413 0.3
4 6 F 17 I MC, BC 0.3
5 1 F 36 III MC 1,200 0.7
6 6 M 18 I MC, BC 0.9
7 93-01 M 77 IV MC, BC 1,000 1.1
8 1 M 63 III BP 223 1.1
9 9 M 50 I MC,BC 180 1.9
10 9 F 24 I MC,BC 2.1
11 9 M 107 III BP 812 2.6
12 9 F 22 I MC 3.3
13 93-01 M 41 IV MC, BC 977 3.4
14 93-01 F 6 I BP 148 3.4
15 9 M 23 II MC, BC 3.4
16 9 M 29 I MC, BC 340 3.6
17 93-01 F 58 III MC 1,220 3.8
18 9 M 50 IV MC, BC 481 4.6
19 93-01 F 83 I MC, BC 68 4.9
20 93-01 F 34 I MC, BC 220 5.0
21 93-01 M 44 IV CN 656 5.2
22 9 F 14 I MC 352 5.5
23 93-01 M 7 I MC, BC 479 7.1
24 1 M 16 I MC 374 8.2
25 93-01 M 38 II MC, BC 500 11.2
26 9 F 18 I MC, BC 120 16.8
27 9 M 31 III DA 445 17.4a
28 9 M 12 I MC 240 20.5a
29 9 M 50 IV MC,BC 2,194 23.4a
30 93-01 M 29 III MC 382 27.6a
31 1 F 18 III MC 540 34.4a
32 6 M 62 III MC
33 9 M 37 I MC, BC 924
34 9 M 26 I MC, BC 225
35 93-01 M 6 II MC, BC 340
36 6 F 21 I MC
37 93-01 F 47 I MC 130
38 93-01 F 35 I MC 5
39 93-01 M 7 III MC, BC 455
40 93-01 F 29 III MC, BC 162
41 93-01 M 4 I BP 381
42 9 F 14 II MC
43 9 M 55 IV MC
44 9 M 13 I MC, BC 400
45 9 M 16 III MC
46 1 F 20 IV MC 733
47 6 M 57 I MC, BC

F, female; M, male; N, normal; E, elevated; MC, mono-, bi-, or triphasic WT, containing blastema, stroma and/or epithelial components; BC,
blastemal-containing WT, but not blastemal predominant; BP, blastemal predominant; CN, complete necrosis; DA, diffuse aplasia (all histology was
performed after preoperative chemotherapy). Elevation of renin is defined as Z-score >1; aFive patients with very high renin levels.
Pediatr Blood Cancer DOI 10.1002/pbc
502 Maas et al.

(81%, median Z-score 3.5 (range 0.9 to 34.4)), whereas 6 patients

had normal levels of renin (19%). In 13 of the 39 WT patients with
normal blood pressure, 5 times renin levels were elevated (median
Z-score 0.33 (range 1.3 to 11.6)) and 8 were normal (P ¼ 0.012).
Of the patients with hypertension 23 patients had stage I, 5 stage II,
12 stage III, and 7 stage IV. Of the patients without hypertension
21 patients had stage I, 10 stage II, 5 stage III, and 3 stage IV
(P ¼ 0.147). In this cohort, 30/50 (60%) boys had an elevated blood
pressure versus 17/36 (47%) girls (P ¼ 0.277). Children with
elevated blood pressure had a median age of 29 months (range 4–
138 months), whereas WT patients with a normal blood pressure had
a median age of 47 months (range 4–116 months) (P ¼ 0.09). The
median body mass index (BMI) of the patients with elevated blood
pressure was 16 (range 14–21) and comparable with the BMI of
nonhypertensive patients (i.e., 15 (range 12–19), n.s.). At diagnosis, Fig. 2. Renin levels and tumor volume (on radiology) in WT patients
all children had a normal serum creatinine. at diagnosis. Elevation of renin is defined as Z-score > 1. The line
After preoperative chemotherapy five patients showed a indicates the median value.
blastemal predominant histology, two patients diffuse anaplasia,
and the other patients showed low or intermediate risk histology
treated with an ACE inhibitor and in 6/7 patients who were treated
(Table I). Of the patients with elevated plasma renin level, 14/30
with propranolol or nifedipine. The blood pressure of 18 of the
patients had a blastema-containing tumor of whom 4 patients were
19 patients not treated before surgery, returned to normal before
blastemal predominant. Of the patients with normal renin levels,
surgery. After tumor nephrectomy blood pressure returned to
5/14 had a blastema-containing tumor.
normal values in all patients but four (91%). In 3 of the 28 previously
Of 36/47 hypertensive patients the tumor volume was available
treated, and 1 of 19 children with untreated hypertension, blood
at diagnosis before starting chemotherapy in this retrospective
pressure remained high after nephrectomy, for which they were
survey and of 21/39 of the normotensive patients. No significant
treated for no more than 3 weeks with an ACE inhibitor, resulting
difference in median tumor volume between both groups was found
in normal blood pressure. At the end of the postnephrectomy
(Fig. 1, P ¼ 0.14). Moreover, no difference was found between the
chemotherapy, none of the patients needed antihypertensive drugs.
tumor volume of WT patients with normal and those with elevated
None of the patients suffered from hypertensive complications, like
renin levels (Fig. 2, P ¼ 0.56). In our study, five patients with
bleeding, cerebrovascular accident or complications related to
very high renin levels were identified (Table I). These five patients
anesthesia or surgery.
were not different from the other patients with respect to age,
gender, histology or other clinical factors like BMI, stage, or tumor
volume. All five received an ACE inhibitor before surgery and
DISCUSSION
showed a very good response.
Twenty-eight of the 47 children with hypertension were treated So far the largest cohort of hypertensive WT patients, in which
with antihypertensive treatment before surgery, that is, 21 children renin was measured consisted of 13 patients (Table I) [3,4]. The
with enalapril (ACE inhibitor), 6 with propranolol (beta-blocker), current study, in which 55% of the 86 patients with nephroblastoma
and 1 with nifedipine (calcium-inhibitor). The patients treated with presented with hypertension, shows an association between
propranolol or nifedipine were patients diagnosed in the period hypertension and high plasma renin levels in WT patients. It should
1982–1990, thereafter an ACE inhibitor was used as hypertensive be emphasized that this is a retrospective study and that renin levels
drug. Blood pressure normalized before surgery in 19/21 patients were not available in all patients. However, the results support the
idea that ACE inhibitors provide an antihypertensive therapy
targeted on the pathophysiology of the hypertension in at least a
subset of WT patients.
The fact that in 91% of our patients blood pressure returned to
normal values after tumor nephrectomy could be explained by the
primary hyperreninaemia hypothesis, that is that renin production
by the tumor is responsible for the hypertension [10,11].
However, also secondary hyperreninaemia may play a role, as
described in congenital mesoblastic nephroma, in which renin
production is observed in normal kidney tissue. This has been
attributed to ischemia secondary to the tumor mass, compression
and stretching of the renal artery branches by an unfavorable tumor
localization, and entrapment of the glomeruli, which activates
the renin-angiotensin-aldosterone system [2,4,11–13]. One could
suggest that in more advanced WT, or in case of extensive invasion
or bulky disease, more renin is produced. However, in our study the
Fig. 1. Tumor volume (on radiology, at diagnosis) in WT patients with tumor volume at diagnosis was not associated with high blood
and without hypertension. The line indicates the median value. pressure and renin levels.
Pediatr Blood Cancer DOI 10.1002/pbc

In general, the cause of hypertension is multifactorial. In WT,
apart from renin, other inducing and regulatory factors like peptide
hormones may play a role in the regulation of blood pressure
[2,4,12,13]. This is underscored by the fact that in our study not all
hypertensive patients showed elevated renin levels. Moreover,
unexpectedly 5/13 normotensive patients showed elevated renin
levels [2,4,12,13].
One study based on immunohistochemistry (ICH) reported
renin expression in the blastemal part in five WT patients [10].
Unfortunately, in that study the relation with hypertension was not
investigated. In our study 66% of the patients with elevated renin
levels and 57% of the patients with normal renin levels had a
blastema-containing tumor. This may suggest that blastema does
not play an important role in renin-induced hypertension in WT.
Unfortunately, no material was available to study renin expression
with ICH. However, it should be taken into account that in the SIOP
studies histological subtypes were assessed after pretreatment with
chemotherapy, which does not reflect the blastemal compartment at
diagnosis. Vujanic et al. [14] showed that treatment prior to surgery
results in a decreased percentage of the blastemal component in WT.
This indicates that the role of blastema in renin production cannot be
derived from this study.
Potentially, WT patients with untreated elevated blood pressure
have a higher risk of complications, like central nervous system
complications, cardiac decompensation, and increased risk of
bleeding before or during tumor nephrectomy [5,15]. This provides
an important rationale for antihypertensive treatment. In our
retrospective study, surprisingly, only 60% of the hypertensive
patients had received antihypertensive treatment before surgery.
From the medical records, it is not clear why individual cases did not
receive antihypertensive treatment. In our series hypertension-
related complications have not been noted before, nor during
surgery. The potential risk of the above-mentioned complications,
however, urges proper treatment.
We conclude that hypertension is renin-related in a substantial
proportion of the WT patients. Prospective studies will be necessary
to investigate the value of ACE inhibitors as the best targeted
treatment for elevated blood pressure in children with WT.
ACKNOWLEDGMENT
We acknowledge Mrs. M. van Leeuwen for her contribution to
this manuscript.
Pediatr Blood Cancer DOI 10.1002/pbc
Renin-Induced Hypertension in Nephroblastoma 503
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