Nephrol Dial Transplant (2005) 20: 1505–1508
doi:10.1093/ndt/gfh864
Advance Access publication 10 May 2005
Nephroquiz
(Section Editor: M. G. Zeier)
Acute renal failure and hypercalcaemia in a man
from Guyana: what is the link?
Case
A 51-year old Guyanese businessman presented with a
5-week history of increasing lethargy, thirst, polyuria
and diffuse symmetrical pain in both small and large
joints. His own doctor prescribed diclofenac for the
arthralgia, and atenolol and bendrofluazide for hypertension. He had migrated to the UK at the age of 18
and had no clinical history of note. His mother had
died aged 57 of unknown cause. On examination, he
was afebrile and clinically hypovolaemic. There was
diffuse small joint tenderness but no other significant clinical findings. Laboratory tests revealed:
leukocytosis of 21.9 109/l (neutrophils 12.3 109/l,
lymphocytes 6.8 109/l), marked hypercalcemia
[calcium adjusted for albumin concentration (ACa)
5.12 mmol/l], phosphate 1.7 mmol/l, serum albumin
35 g/l and renal dysfunction [urea 17.9 mmol/l,
creatinine 206 mmol/l (2.34 mg/dl)]. One month earlier,
his urea had been 4.9 mmol/l and creatinine 82 mmol/l
(0.93 mg/dl). His 24 h urine volume was 6 litres with a
protein excretion of 0.4 g/24 h and creatinine clearance
47 ml/min. Blood film showed a lymphocytosis
with pleomorphic morphology, but bone marrow
trephine showed only hypercellular marrow with
reactive non-specific changes. All medication was
stopped on admission and he was fluid resuscitated.
Pamidronate (60–90 mg) was administered on six
occasions over a period of 1 month. Though renal
function improved [urea 5.5 mmol/l, creatinine
(92 mmol/l, 1.04 mg/dl)], ACa remained consistently
>3.00 mmol/l.
Our patient’s resistant hypercalcaemia was
investigated and a number of hormones and
cytokines involved in calcium homeostasis were
measured using standard chemistry assays (Roche,
Lewes, UK) and commercial immunoassays (Nichols,
San Juan Capistrano, USA, R & D Systems, UK,
Biomedica, GmbH): parathyroid hormone (PTH)
0.3 pmol/l (0.5–5.5), 25-OH-vitamin D 29 nmol/l
(>50), 1,25-(OH)2-vitamin D 38 nmol/l (43–144),
PTH-related peptide (PTHrP) 6.3 pmol/l (<1.8),
interleukin-6 (IL-6) 4.6 pg/ml (<3), receptor activator
of nuclear factor-kB ligand (RANKL) 1.3 pmol/l
(0.7–1.2), osteoprotegerin (OPG) 8.3 pmol/l (2.7–3.2),
tumour necrosis factor-a (TNF-a) 2.9 pg/ml (<15.6)
and soluble TNF receptor-1 (sTNFR-1) 3787 pg/ml
(512–1739).
Radiographs of the sites of bony tenderness
were taken (Figure 1). An isotope scan of the
parathyroids was normal, and computed tomography
(CT) scan of his neck, thorax and abdomen showed
a non-obstructing right renal calculus but no other
abnormalities.
Questions
(i) What does the X-ray show?
(ii) What serological test would be useful?
(iii) What is the diagnosis?
Correspondence and offprint requests to: Dr J. B. Eastwood,
Department of Renal Medicine, St. George’s Hospital, Blackshaw
Road, London SW17 0QT, UK. Email: [email protected]
ß The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
For Permissions, please email: [email protected]
1506
J.-h. Wang et al.
Fig. 1. X-ray of the right hand showing the metacarpal bones and adjacent joints.
Answer to the quiz on the preceding page
The radiograph shows both subperiosteal bone
resorption and widespread discrete 1–2 mm diameter
foci of cortical loss. X-rays of the distal forearm bones
showed similar changes. Subperiosteal erosions, especially on the radial aspect of the middle phalanx of
the middle and index fingers, are pathognomonic of
hyperparathyroidism. Furthermore, in hyperparathyroidism, there can be intra-cortical bone loss in the
form of ‘brown’ tumours. However, in our patient,
the radiologically discrete areas of cortical loss are
far too small to be considered to be ‘brown’ tumours.
In addition, the apparently normal bone density on the
X-ray and the extensive involvement of the metacarpal
bones rules out hyperparathyroidism. There are a
number of other causes of bone resorption. In myeloma, the lesions are ‘punched out’ and rarely affect the
peripheral skeleton. Sarcoidosis produces a lace-like
pattern of bone loss unlike the appearances in Figure 1.
The sparing of the joints in our patient also excludes
erosive arthropathies such as osteoarthritis and rheumatoid arthritis. Clearly, in our patient, the priority
was to exclude a neoplastic cause for his bone disease.
In view of the patient’s country of origin, antibodies
to human lymphotropic T-cell virus type 1 (HTLV-1)
were sought; they were positive. A diagnosis of acute
adult T-cell leukaemia/lymphoma (ATLL) was made;
immunophenotyping (CD2þ/HLA-DRþ ¼ 85%) was
diagnostic of HTLV-1 infection. Our patient’s illness,
therefore, was a clear example of ATLL-related
humoral hypercalcaemia of malignancy (HHM).
Prognosis of patients with ATLL is poor. The
median survival is 8 months, and the 4-year survival
is only 12% even when treated optimally. Our patient
had a particularly aggressive and resistant form of
the disease and he underwent multiple regimens of
chemotherapy including CHOP (cyclophosphamide,
doxorubicin, vinicristine, prednisolone), PitMiCEBO
(mitoxantrone, cyclophosphamide, etoposide, bleomycin, vinicristine, prednisolone), DHAP (dexamethasone, cisplatin, cytarabine) and EMI (epirubicin,
etoposide, ifosfamide, mesna). He was also given
CAMPATH (CD52 monoclonal antibody), and a
combination of interferon-a with combivir (zidovudine
and lamivudine), the latter regimen having been
shown to be beneficial in recent studies. Sadly, our
patient failed to improve and died 3 months after
presentation.
Hypercalcaemia is common in certain haematological malignancies and occurs in up to 80% of cases
of ATLL, a condition closely associated with HTLV-1
infection [1]. This virus is endemic in the southern
Caribbean (where our patient was born) and Japan.
It can be transmitted both sexually and through
blood contamination, but in our patient vertical
transmission, during pregnancy or breast-feeding [2],
is most likely. In patients acquiring HTLV-1 infection
at an early age, there is a 2–4% lifetime risk of
developing ATLL [3]. The fact that our patient was
ARF and hypercalcaemia in a man from Guyana
completely well until presentation is consistent with
the known latent period of at least 20 years between
infection and disease manifestation [4].
HHM is a consequence of calcium release secondary to accelerated widespread bone resorption [5].
A number of cytokines, also expressed by ATLL
cells, can induce proliferation of the bone-resorbing
osteoclast, but until recently it was not clear which
ones were responsible for directly initiating osteoclastogenesis. Osteogenic factors previously postulated
include IL-1, IL-2, IL-6, TNF-a, macrophage colonystimulating factor (M-CSF) and PTHrP [6,7]. It is
now clear that the elusive osteoclastic differentiation
factor is the well-known ligand, RANKL [8]. Expressed
by pre-osteoblastic and stromal cells, RANKL binds
to its receptor RANK on the surface of pre-osteoclast
lineage cells and pre-fusion osteoclasts to initiate
differentiation to osteoclasts. The process is moderated
by OPG (a soluble protein secreted by osteoblasts),
which acts as a decoy receptor for RANKL [9].
PTH can be low in HHM, whereas PTHrP, which
has a partially identical sequence (13 amino acids) in
the active domain to PTH and shares the same receptor
(PTH1-R), can be significantly elevated [10]. This
was the case in our patient. In vivo, PTHrP increases
bone resorption and renal tubular reabsorption of
calcium. In addition, cytokines such as IL-6, IL-1 and
TNF have been shown to have a synergistic action with
PTHrP [11,12]. However, PTHrP alone does not
appear to increase the numbers of osteoclasts and it
has not been shown convincingly that osteoclasts
express PTH receptors; hence, direct osteoclast activation by PTHrP is unlikely.
Circulating IL-6, TNF-a and PTHrP were increased
in our patient, and the overall synergistic effect
could explain the extreme hypercalcaemia observed.
Surprisingly, for such severe hypercalcaemia, both
RANKL and TNF-a levels were not significantly
elevated in the presence of high OPG and sTNFR-1
levels. However, since each assay measures only the
free fraction of the molecule, it is possible that the
bound (unmeasured) portion of RANKL/TNF-a was
high. The significance and role of sTNFR-1 in
osteoclastogenesis have yet to be defined.
We did not check for the presence of tax, a viral
gene product that is expressed in tumour cells transformed by HTLV-I in vivo. Tax, although it induces
the expression of a wide range of host cell gene
products—including cytokines, transcription factors
and membrane proteins and receptors—is not associated with the expression of the RANKL gene [13].
Although some patients with ATLL have elevated
levels of 1,25-(OH)2-vitamin D as a result of increased
1a-hydroxylase activity, the majority, like our patient,
have suppressed 1,25-(OH)2-vitamin D levels. Elevation
of 1,25-(OH)2-vitamin D levels, therefore, is not a
contributory factor in the hypercalcaemia.
This case highlights the complexity of the pathophysiology of HHM and the advances that have been
made in its understanding. It should be mentioned
that OPG has shown promising therapeutic effects
1507
in malignant, rheumatic and post-menopausal bone
disease and also in inhibiting the apoptosis of myeloma
and cancer cells in vitro.
Our patient is unusual in presenting with
symptoms secondary to hypercalcaemia but with no
obvious clinical features of ATLL—lymphadenopathy,
skin lesions or organomegaly; also, there were no
constitutional symptoms of lymphoma. The important
clue in making the correct diagnosis was his
country of origin. This case underlines the importance
of considering all aspects of a patient’s history. It also
illustrates the paradox of having a very long period
of asymptomatic HTLV-1 infection culminating in a
short fulminating final phase of acute ATLL.
Several questions are raised by this patient’s case.
Since HTLV-1 is sexually transmitted, should his wife
be screened? Indeed, should individuals at risk, including the newborn, be screened routinely? Currently in
the UK, there is no widespread screening of individuals
from endemic areas. However, in August 2002, HTLV1 screening was introduced by the National Blood
Service for all donations of blood products, and for
certain donor tissue—cornea, skin, bone and heart
valves [14,15]. Yet, for solid organs, neither the UK nor
Eurotransplant tests for HTLV-1 infection. Should
they not now be doing so?
Acknowledgements. We thank the patient’s wife for encouraging
us to publish details of her husband’s illness. We are also grateful
to Dr Dupe Elebute for her comments on the HTLV-1 aspects of
the paper.
Conflict of interest statement: None declared.
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J.-h. Wang et al.
Jia-hui Wang1
Michael Pazianas3
William D. Fraser2
Fiona Harris1
John B. Eastwood1
1
Department of Renal Medicine
St George’s Hospital
Blackshaw Road
London SW17 0QT
2
Department of Clinical Biochemistry
University of Liverpool
Liverpool L69 3BX
UK
3
Department of Medicine
University of Pennsylvania
3615 Chestnut St
Philadelphia
PA 19104
USA