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Original Article

A case report of reninoma: radiological and
pathological features of the tumour and
characterization of tumour-derived juxtaglomerular
cells in culture
Emmanuelle Vidal-Petiot a,b, Marcelle Bens b, Laurence Choudat c, Pedro Fernandez d,
Franc¸ois Rouzet e, Jean-Franc¸ois Hermieu f, Patrick Bruneval g, Jean-Michel Goujon h,
Martin Flamant a,b, and Alain Vandewalle b

Case report: A 20-year-old woman presented with
malignant hypertension associated with hypokalemia,
metabolic alkalosis and elevated plasma renin and
aldosterone levels. Computed tomography angiography
(CTA) evidenced a 22 mm tissular mass in the posterior
cortex of the left kidney, and 18F-flurodeoxyglucose PET
(18-FDG PET) imaging showed no hypermetabolism of the
tumour. Following nephron-sparing surgery, blood pressure
and potassium levels rapidly normalized, allowing
interruption of all treatments within 2 weeks.
Discussion: Reninoma is a rare juxtaglomerular cell
tumour (JGCT) producing excessive amounts of renin
resulting in severe hypertension. Pathological studies
revealed that tumoural cells highly expressed renin and
contained electron-dense structures, typical of renincontaining granules. Tumoural cells also exhibited the
vascular cell surface marker CD34, but, in contrast with
previous reports, did not express the tyrosine-protein
kinase Kit (cKit or CD117). Dissociation of the tumour
allowed to obtain confluent cultures of elongated smooth
muscle actin (SMA)-positive cells producing high amounts
of renin. However, after the first passage, subcultured
human juxtaglomerular cells rapidly lost renin and CD34
expressions and their ability to produce renin.
Conclusion: The present case of reninoma emphasizes the
need for CTA in the etiologic work up of otherwise
unexplained severe hypertension. 18-FDG PET imaging
showed no hypermetabolism of the tumour, in accordance
with its reported benignity. Pathological studies further
emphasized that high expressions of renin and CD34 are
typical hallmarks of reninoma. Although CD117 has been
proposed to represent a reliable marker of JGCT, the
present findings indicate that reninomas may not always
express this marker.
Keywords: CD34, hypertension, juxtaglomerular cells,
renin, reninoma
Abbreviations: 18-FDG PET, 18F-flurodeoxyglucose PET;
BP, blood pressure; CTA, computed tomography

angiography; JGCT, juxtaglomerular cell tumour; MSC,
mesenchymal stem cells; SMA, smooth muscle actin

INTRODUCTION

R

eninoma is a benign juxtaglomerular cell tumour
(JGCT) that constitutively produces high amounts of
renin, causing secondary hyperaldosteronism, and
severe hypertension with hypokalemia and metabolic alkalosis [1,2]. Since the first description by Robertson et al. in
1967 [3], approximately a hundred cases have been
reported [4]. Surgical removal of the tumour by total or
partial nephrectomy has been shown to efficiently remove
reninomas. Although several studies have described the
main morphological and ultrastructural features of reninomas, the exact origin of JGCT still remains elusive. Here, we
report a case of reninoma in a young woman with detailed
clinical, radiological and pathological findings, and the
main features of the tumoural cells in culture.

CASE REPORT
A 20-year-old woman of African origin presented at the
emergency department with headaches and blood pressure
(BP) of 230/130 mmHg. She also reported polyuria and
polydipsia for a few days. She had no family history of
Journal of Hypertension 2015, 33:1709–1715
a

De´partement de Physiologie, DHU Fire, Hoˆpital Bichat, AP-HP, Paris, bINSERM,
U1149, Centre de Recherche sur l’Inflammation, Univ. Paris Diderot, Sorbonne Paris
Cite´, Paris, cDe´partement de Pathologie, dDe´partement de Radiologie, Hoˆpital Bichat,
Paris, eDe´partement de Me´decine Nucle´aire, Hoˆpital Bichat, AP-HP, Univ. Paris
Diderot, Paris, fService d’Urologie, Hoˆpital Bichat, AP-HP, Paris, gDe´partement de
Pathologie, Hoˆpital Europe´en George Pompidou, AP-HP, Universite´ Paris 5, Paris and
h
Anatomie et Cytologie Pathologiques, CHU, Universite´ de Poitiers, Poitiers, France
Correspondence to Dr Emmanuelle Vidal-Petiot, De´partement de Physiologie-Explorations Fonctionnelles, Hoˆpital Bichat, 46 rue Henri Huchard, Paris 75018, France. Tel:
+33 1 40258408; fax: +33 1 40258856; e-mail: emmanuelle.vidal-petiot@
bch.aphp.fr
Received 23 December 2014 Revised 4 March 2015 Accepted 4 March 2015
J Hypertens 33:1709–1715 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights
reserved.
DOI:10.1097/HJH.0000000000000592

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hypertension, but presented a personal history of elevated
BP for 1 year, attributed to a white-coat effect with no
treatment initiated. She denied any alcohol intake, smoking
or street drugs abuse. She had no other cardiovascular
risk factor.
Fundoscopic examination of the retina showed bilateral
papillar oedema, establishing the diagnosis of malignant
hypertension. Biochemical analysis revealed a blood potassium of 2.1 mEq/l with inappropriate kaliuresis. Plasma
creatinine was 0.57 mg/dl. She had glomerular proteinuria,
with a urinary albumin-to-creatinin ratio of 184 mg/mmol.
Troponin was slightly elevated (0.68 mg/l), but with a
normal electrocardiogram. Other biological parameters
were unremarkable, in particular she had no sign of thrombotic microangiopathy. Echocardiography revealed concentric left ventricular hypertrophy, with a left ventricular
mass of 136 g/m2 (normal <95 g/m2) without evidence of
aortic coarctation. Brain MRI evidenced periventricular and
subcortical white matter hyperintensities on T2-weighted
and FLAIR images. After intravenous medication including
potassium, nicardipine and rehydration with isotonic
saline, the patient was given oral treatment with potassium
chloride, ramipril, bisoprolol and amlodipine. BP rapidly
improved in a few hours and was thereafter controlled
under treatment, and kalemia returned to normal values
within 10 days. The 24 h urinary metanephrine levels were
normal, and a hypercorticism was ruled out by a cortisol
cycle and dexamethasone suppression test. Plasma renin
and aldosterone levels were extremely elevated both in
supine and upright position (renin: 295 and 419 pg/ml;
aldosterone: 1162 and 1389 pg/ml, respectively). Doppler
imaging of the renal arteries and noninjected computed
tomography were considered normal.
One month after the initial event, BP was controlled
(120/82 mmHg on average in a 24 h ambulatory BP monitoring) under triple antihypertensive therapy (ramipril, bisoprolol, and amlodipine). We allowed a 6-month recovery
period after the malignant hypertension event before a new
diagnostic evaluation. For this purpose, the treatment was
replaced by drugs that do not interfere with the reninangiotensin system, namely diltiazem, urapidil and rilmenidine, as well as potassium chloride supplementation, for a
2-week period. During this period, BP gradually increased
and the patient had a relapse of metabolic alkalosis
(bicarbonate level 30 mmol/l) and hypokalemia
(3.2 mmol/l), associated with moderate polyuria (2.9 l/
24 h). Glomerular filration rate (GFR) measurement with
plasma clearance of 51CrEDTA showed hyperfiltration
(132 ml/min per 1.73 m2), associated with glomerular proteinuria (1.8 g/day). Free plasma and urinary metanephrines
were once again strictly normal. Renin and aldosterone levels
remained extremely elevated, both in 2 h supine and upright
position (renin: 286 and 311 pg/ml; aldosterone: 248 and
929 pg/ml, respectively). Such elevated values outside of a
malignant hypertension episode were highly suggestive of a
renin tumuor. Computed tomography angiography (CTA)
showed normal renal arteries with no sign of fibromuscular
dysplasia, but revealed a 22 mm renal mass lesion isodense to
the renal parenchyma, with weak contrast enhancement in
the posterior face of the left kidney (Fig. 1a–d). The renal
tumour also appeared heterogeneous by MRI, with a high
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signal intensity on T2-weighted imaging (Fig. 1e), iso-signal
intensity on T1-weighted imaging (Fig. 1f), with weak but
significant, heterogeneous contrast enhancement after contrast medium injection (Fig. 1g–i). In addition, diffusionweighted imaging revealed hypersignal intensity with a
reduction of apparent diffusion coefficient (not shown).
18F-flurodeoxyglucose PET (18-FDG PET) imaging revealed
no hypermetabolic activity of the tumour (Fig. 1j–l).
The patient underwent laparoscopic left partial nephrectomy to remove the tumour, without any intraoperative
or postoperative complication. The treatment was diminished progressively after the surgery and completely interrupted within 2 weeks. Three months after the surgery and
cessation of all treatments, ambulatory BP measurement
showed an average BP of 117/79 mmHg, microalbuminuria
was normalized, fundoscopy was normal and cardiac
hypertrophy has resolved with a left ventricular mass of
89 g/m2. Supine renin was 3.9, 3.8, 4.7 and 3.3 pg/ml, and
supine aldosterone was 26, 49, 44 and 45 pg/ml, 5 days, and
3, 5 weeks and 3 months after surgery, respectively.

PATHOLOGICAL STUDIES
Gross examination revealed a solitary, well circumscribed
and nonencapsulated tumour measuring 22 mm, which was
localized in the superficial cortex, with a mostly yellow-tan
coloured section and some areas of haemorrhage and cysts
(Fig. 2a and b). The tumour was composed of solid sheets
of closely packed polygonal cells with eosinophilic cytoplasm, and large round to oval nuclei of unequal sizes. Rare
and moderate nuclear atypia could be seen, but mitotic
figures were rare. A few entrapped pseudo-tubules were
identified (Fig. 2c). The tumour exhibited a diffuse and
intense positive cytoplasmic staining using a mouse monoclonal antirenin antibody, whereas renin staining in the
juxtaglomerular apparatus from the nontumoural parts of
the kidney was undetectable (Fig. 2d–f). Electron microscopic examination also revealed numerous electron-dense
irregular dark granules typical of renin-secretion granules
(Fig. 2g and h).
A strong diffuse immunoreactivity was evidenced for the
vascular marker CD34 (Fig. 3a). In contrast, not all tumoural
cells were immunoreactive to smooth muscle actin (SMA)
(Fig. 3b). Furthermore, tumoural cells did not express the
cell surface tyrosine kinase growth factor receptor CD117,
in contrast with the intratumoural mast cells that served as
positive controls (Fig. 3c). All tumour cells stained negative
for cytokeratin7, whereas the intratumoural pseudo-tubules
were strongly positive for this epithelial marker (Fig. 3d).
Only very few tumoural cells exhibited positive staining
using the anti-Mib1 antibody directed against the proliferation related Ki67 antigen (Fig. 3e), whereas tumoural cells
diffusely expressed the intermediate filament vimentin
(Fig. 3f), that is expressed in mesenchymal cells.

CULTURED HUMAN
JUXTAGLOMERULAR TUMOUR CELLS
Because only very few studies have analysed the features
of human reninomas in culture [5,6], a portion of the
tumour was used to establish primary and subcultures of
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Case report of reninoma

(a)

(b)

(c)

*

(e)

(f)

(j)

*

(g)

*

*

(d)

*

(h)

*

(i)

*

(k)

*

(l)

FIGURE 1 Imaging studies of the tumour. (a–d) Computed tomography (CT) angiography of the left kidney, precontrast (a) and during the arterial (b), parenchymal (c) and
excretory (d) phases after injection, showing a 22 mm renal mass lesion isodense to the renal parenchyma, visualized only after contrast enhancement as a hypovascular
tumour with a weak contrast enhancement. (e–i) MRI of the left kidney showing a heterogeneous high signal intensity mass on T2-weighted imaging (e), isointense on
T1-weighted imaging (f), with weak and heterogeneous contrast enhancement during arterial (g), parenchymal (h) and excretory (i) phase. (j–l) 18-FDG PET/CT imaging
showing no hypermetabolic renal cortical lesion. Red lines indicate the tumour. k and l represent axial and sagittal fusion images. athe tumour.

juxtaglomerular cells. Under sterile conditions, part of the
tumour was minced into small pieces and incubated in a
hormonally, defined medium containing 10% foetal calf
serum and supplemented with 0.2% collagenase for 1 h at
378C as described [7]. Cell homogenates were passed through
a 70 mm pore-sized filter and centrifuged. The resulting cell
suspension was then seeded on 12-well trays and grown in
defined medium. The medium was changed after the first 5
days of culture and every 2 days thereafter. Growing cells
formed rapid layers of confluent elongated shaped cells 15
days after seeding (Fig. 4a). Confluent primary cultured
juxtaglomerular cells synthetized very high amounts of renin,
measured by radioimmunoassay on cell supernatants
(Fig. 4b). All wells of confluent cultured cells could be easily
passaged and still formed confluent layers of elongated cells.
However, the production of renin dropped dramatically in
confluent subcultured cells (not shown). Indirect immunofluorescence studies also showed that subcultured juxtaglomerular cells (first and second passages) were composed of
100% SMA-positive cells (Fig. 4c), but only a few cells (less
Journal of Hypertension

than 1%) still exhibited a typical cytoplasmic granular renin
positive staining (Fig. 4d and e).

DISCUSSION
Reninoma is an extremely rare, benign renin-secreting
tumour from the juxtaglomerular apparatus, which occurs
mainly in young adult women with a 2 : 1 sex ratio and a
mean age of 25 years [4,8]. Hypertension is a constant
clinical feature, with a mean duration of 4–6 years at the
time of diagnosis. In rare cases, hypertension was first
detected during pregnancy, with a grim prognosis [9].
The most common associated symptoms are headache,
nausea, polyuria, excessive thirst and fatigue, although in
some patients, hypertension is the only symptom. Endorgan damage, such as hypertensive retinopathy, proteinuria, renal insufficiency and left ventricular hypertrophy
are not uncommon. Hypokalemia is present in approximately 80% of the cases and often severe. However, as
stated by Wong et al. [4], the diagnosis of a reninoma should
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(a)

(b)

(c)

(d)

(e)

(f)

MD
G

(g)

(h)

FIGURE 2 Histology of the renin-secreting tumour. (a) The tumour formed a well expanding cortically yellow-tan solid nodular mass with irregular areas of haemorrhage.
Bar ¼ 1 cm. (b and c) The tumour was composed of predominant round-shaped cells with eosinophilic cytoplasm (hematoxylin & phloxine staining), associated with
entrapped sections of tubule epithelial cells (c, arrow). (d–f) Intense diffuse renin immunostaining in tumour cells (d and e). In contrast, no renin staining was detected in
juxtaglomerular apparatus from the nontumoural part of the kidney (arrows, f). (g and h) Electron microscopic illustrations showing elongated and round-shaped cells with
large nuclei and numerous electron-dense irregular dark granules typical of renin-secretion granules (arrowheads). G, glomerulus; MD, macula densa. Bars ¼ c, d, f,
100 mm; g, 1 mm; h, 0.1 mmol/l.

(a)

(b)

(c)

(d)

(e)

(f)

FIGURE 3 Immunohistochemical characteristics of the tumour. (a–d) Illustrations at low and high magnification (20 ) of the immunostaining using antibodies directed
against CD34 (a), smooth muscle actin (b), CD117 (c), cytokeratin 7 (d), Mib-1 (e) and vimentin (f). All tumoural cells highly expressed CD34, but none exhibited positive
CD117 immunoreactivity. The few CD117-positive cells corresponded to mast cells (internal positive controls, arrowheads). Very few tumoural cells exhibited positive
immunostaining using the anti-Mib1 antibody (e, arrowheads)). Bars ¼ 100 mm.

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(a)

(b)

Renin production (pg/ml)

Case report of reninoma

5000
4000
3000
2000
1000
0
0

120

240

360

Time (min)
(c)

(d)

(e)

FIGURE 4 Renin production by cultured human juxtaglomerular cell tumor. (a) Primary cultures derived from the reninoma formed confluent layers of elongated cells.
(b) Renin production as a function of time by primary cultured human juxtaglomerular cells. Values are the mean from three separate wells. (c) Subcultured (first passage)
human juxtaglomerular cells exhibited positive SMA immunoreactivity (in red). Nuclei were stained in green. (d and e) Renin immunofluorescence staining forming dense
granular cytoplasmic staining in subcultured juxtaglomerular cells (first passage). As a control, no positive staining was detected by omitting the primary antibody (e, insert).
Bars (a, c–e) ¼ 10 mm.

be considered even in the absence of hypokalemia, as the
serum potassium level may be affected by the antihypertensive treatment. Renin levels are markedly increased,
more than 10 times the upper limit of normal on average,
but aldosterone levels, also elevated on average, are more
variable [4]. Patients are highly sensitive to converting
enzyme inhibitors [8]. Hypertension is usually reversible
after surgical cure of the tumour, whereas evaluation of
reversibility of end-organ damage has rarely been reported.
In this clinical case, the reninoma occurred in a young
female patient who presented with malignant hypertension, extremely high renin and aldosterone levels, and
marked hypokalemia, with a high sensitivity to pharmacological blockade of the renin-angiotensin system. A secondary hyperaldosteronism is expected during the course of
any malignant hypertension, but in the present case, it was
particularly severe, and it persisted even after 6 months of
efficient medical treatment of hypertension. In this setting,
the finding of a renal mass lesion in the absence of a renovascular disease almost ascertained the high suspicion of a
reninoma. As underlined in a previous report, noncontrastenhanced CT/MRI of the kidney is not sufficient to rule out a
renin tumour, which may be isodense/isointense to the
renal parenchyma [10]. Interestingly, this is to our knowledge the first report of 18-FDG PET imaging in a reninoma,
and it indicated no hypermetabolism of this nonproliferative, benign tumour. After radical or partial nephrectomy,
almost no recurrence of JGCT has been reported in the
literature, with the exception of extremely rare malignant
reninomas [11,12]. After surgery, the BP of the patient
returned rapidly to normal levels, without the need of
antihypertensive treatment. However, persistent mild hypertension has been reported in about 10% of patients after
tumour resection [13].
In accordance with previous reports, the reninoma that
we analysed displayed high and diffuse expressions of
renin and CD34. In contrast to the tumour cells that highly
Journal of Hypertension

expressed renin, no positive renin staining was detected in
juxtaglomerular apparatus located in the neighbouring
nontumoural part of the kidney. This suggests that the high
amounts of renin produced by deregulated tumour cells
inhibit renin secretion in intact nephron units via an inibitory feed back mechanism. A number of studies also
reported a high expression of CD117, which has been
proposed, together with renin and CD34 expression, to
be a diagnostic tool for the diagnosis of reninoma [14]. In
the present case, immunostaining for CD117 was negative,
suggesting that not all reninomas overexpress CD117. A
review of the literature with a focus on pathological features
of reninomas actually reveals previous reports of negative
immunostaining for CD117 [13,15]. Therefore, a positive
CD117 immunostaining does not represent an absolute
criterion for the diagnosis of reninomas. Rather, it appears
that renin immunoreactivity, the presence of renin-secreting granules by electron microscopy and a high CD34
expression are cardinal pathological features for the diagnosis of reninoma in keeping that hemangiopericytoma,
renal cell carcinoma and Wilms tumour can also exhibit
positive renin and/or CD34 immunoreactivity, and in some
cases may induce hypertension [13,16].
Primary cultures of renin-secreting cells have been
obtained from rat and mouse kidneys [17–19], and also
from a human renin tumour [5,20]. Immortalized human
juxtaglomerular cells derived from primary cultures of a
human reninoma transfected with various simian Virus 40
(SV40) mutants have also been established [5,6]. Primary
cultures of juxtaglomerular cells were shown to produce
high amounts of renin, but in all cases, renin production fell
to almost zero after the first passage. In the present case,
confluent cultures of juxtaglomerular cells could be easily
established. Primary cultures produced high amounts of
renin. However, as in previous studies [5], the production of
renin rapidly fell in subcultured cells after the first passage.
Interestingly, only very few cells exhibiting positive
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Vidal-Petiot et al.

granular renin staining could be detected in juxtaglomerular cells subcultured after the first passage. These findings
emphasize the difficulty to maintain renin expression in
subcultured human juxtaglomerular tumour cells.
The exact pathogenesis of JGCT still remains unknown. In
accordance with previous studies, the present nonmetabolically active reninoma exhibited almost no proliferative
capacity, but highly expressed vimentin. Vimentin is an
intermediate filament early expressed in cells of mesodermal
origin and in a variety of nontumoural and tumoural cells
with high proliferative capacities [21–23]. In accordance with
the high and diffuse expression of CD34, shown to be
expressed in blood and bone marrow derived progenitor
cells [24,25], the fact that the nonproliferative reninomas
highly express vimentin further confirm that JGCT originate
from mesenchymal stem cells. The nuclear hormone receptor liver X receptor alpha (LXRalpha) has been shown to be a
transcriptional regulator of renin, as well as of the transcription factor c-myc, and of a number of genes involved
in growth and differentiation processes. Matsushita et al. [26]
showed that the activation of LXRalpha stimulates renin gene
expression in human and murine juxtaglomerular cells.
Prolonged cAMP stimulation of murine mesenchymal stem
cells (MSCs) overexpressing LXRalpha induced the differentiation of MSCs into juxtaglomerular-like cells containing
renin in secretory granules that was released after cAMP
stimulation [26], further suggesting that juxtaglomerular cells
are derived from MSC. Recently, Kuroda et al. [15] reported
an immunohistochemical and genetic study of six cases of
reninoma. They observed a loss of chromosome 9 in four of
the six cases analysed. Consistent with the immunohistochemical findings, whole genome expression of two reninomas also revealed an upregulation of a large number of
genes, including CD117. They conclude that the loss of
chromosome 9 and loss of expression of some tumour
suppressor genes on chromosome 9 might be involved in
the pathogenesis of reninomas. Further studies will be
needed to better characterize the pathophysiological features of JGCT, however limited by the very rare occurrence of
such tumours.

ACKNOWLEDGEMENTS
We thank Veronique Naizondard and Pascale Soule´ for
renin measurements, Nathalie Quellard for electron microscopy facilities, Dr Ve´ronique Albano for microscopic illustrations, Dr Sonia Bergaya for the gift of SMA antibody and
Dr Melinda Majlath for their help with interpretation of
imaging studies.
There are no sources of funding to declare.

Conflicts of interest
There are no conflicts of interest.

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Volume 33 Number 8 August 2015

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Case report of reninoma

Reviewers’ Summary Evaluations
Referee 1
Strengths
- The authors perform an extensive clinical, radiological,
histopathological and molecular characterization of a case
of malignant hypertension due to a reninoma.
- It helps to advance the knowledge of this rare cause of
secondary hypertension and may serve as a diagnostic
reference to other cases (e.g. first PET-TC imaging documented of this tumor).

Journal of Hypertension

Weaknesses
- The authors studied a single case so that the data
presented should be extrapolated with caution when confronted with other cases.

Referee 2
This presentation may be considered as one of the most
extensive and well documented, providing an excellent
overview of this rare form of secondary hypertension.

www.jhypertension.com

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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