Nephrol Dial Transplant (2004) 19: 2929
1
Paris Albert Bensman
France
Email: tim.ulinski@trs.ap-hop-paris.fr
1. Shalev H, Romanovsky I, Knoers NV et al. Bladder function
impairment in aquaporin-2 defective nephrogenic diabetes
insipidus. Nephrol Dial Transplant 2004; 19: 608–613
2. Ramsey EW, Morrin PA, Bruce AW. Nephrogenic diabetes
insipidus associated with massive hydronephrosis and bladder
neck obstruction. J Urol 1974; 111: 225–228
3. Tank ES, Alexander SR, Craven RM. Polyuric megalocystis.
J Urol 1980; 124: 692–694
4. Eika B, Levin RM, Longhurst PA. Comparison of urinary
bladder function in rats with hereditary diabetes insipidus,
streptozotocin-induced diabetes mellitus, and nondiabetic osmo-
tic diuresis. J Urol 1994; 151: 496–502
5. Zerin JM, Chen E, Ritchey ML et al. Bladder capacity as
measured at voiding cystourethrography in children: relation-
ship to toilet training and frequency of micturition. Radiology
1993; 187: 803–806
doi:10.1093/ndt/gfh486
Hypercalcaemia from non-prescription vitamin A
Sir,
Use of over-the-counter ‘natural’ supplements may have
unnatural effects. We report this case as a cautionary
example.
A 67-year-old white man was admitted to hospital in
late January 2004, with malaise and hypercalcaemia. He
had undergone kidney transplantation 6 years earlier for
kidney failure of unknown cause. Chronic allograft nephrop-
athy occurred and the plasma creatinine rose to 400 mmol/l.
He began to feel unwell in December 2003, and had a 5 kg
weight loss. There was constipation, melena and haemato-
chezia. His medications included prednisone, mycophenolate
mofetil, atorvastatin, labetalol, bumetanide and potassium
chloride. Blood tests showed a total plasma calcium of
4.2 mmol/l and he was admitted to hospital. On examination,
there was a tremor and unsteadiness of gait. The plasma
creatinine was 450 mmol/l. The ionized calcium level was
1.7 mmol/l (normal 1.2–1.3). Intravenous normal saline was
given. Chest X-ray was normal. Upper and lower gastro-
intestinal endoscopy showed antral gastritis and two benign
colonic polyps. Serum and urine protein electrophoresis
did not show a paraprotein. The parathormone (PTH) level
was 17 pg/ml, (normal 10–65) and that of PTH-related
peptide was undetectable. The total plasma calcium reached
2.5 mmol/l by hospital day 4. On that day, further enquiry
showed that he had been taking a dietary supplement
containing vitamin A, on the advice of an eye doctor, for
the possible diagnosis of macular degeneration. This over-
the-counter supplement contains 7000 U of b-carotene
per tablet and he had been taking four tablets daily since
the autumn of 2003. Because of the possibility of vitamin
A-induced hypercalcaemia, this supplement was stopped
immediately. A retinol plasma level was 2550 mg/l (expected
values 350–1200). A month later, he was feeling his usual self,
the total plasma calcium had fallen to 2.4 mmol/l, and the
plasma creatinine had fallen to 400 mmol/l.
The increasing use of dietary supplements and over-
the-counter medicines, ‘natural’ or otherwise, may pose
significant risks. In this case, the total daily dose of vita-
min A that this patient was using was 28 000 U, whereas
2929
the recommended daily intake is only 5000 U. The associa-
tion of vitamin A toxicity and hypercalcaemia is rare but
well recognized. We found only eight case reports of this
association in the past 30 years, the most recent being in
1988 [1].
The hypercalcaemia of vitamin A toxicity may occur
because of activation of bone resorption by vitamin A [2].
This man’s reduced baseline kidney function may have
predisposed him to vitamin A toxicity. Given the modern
prevalence of use of alternative medicines and supple-
ments, more such cases may occur, which emphasizes the
ongoing importance of vigilance and a careful medication
history.
Conflict of interest statement. None declared.
Department of Medicine Eric P. Cohen
Medical College of Wisconsin Chinmaya Trivedi
Milwaukee
WI
USA
Email: ecohen@mcw.edu
1. Bergman SM, O’Malia J, Krane NK et al. Vitamin A induced
hypercalcemia: reponse to corticosteroids. Nephron 1988; 50:
362–364
2. Frame B, Jackson CE, Reynolds WA, Umphrey JE.
Hypercalcemia and skeletal effects in chronic hypervitaminosis
A. Ann Intern Med 1974; 80: 44–48
doi:10.1093/ndt/gfh437
A fatal case of aluminium encephalopathy in a patient
with severe chronic renal failure not on dialysis
Sir,
Aluminum (Al) toxicity in patients with end-stage renal
disease is a well known adverse effect due to either
dialysate Al contamination or oral intake of Al-containing
phosphate binders [1]. At present, the clinical forms of Al
toxicity have almost disappeared. Al-containing drugs are
given mainly as antacid agents and are often used without
special caution in patients with chronic renal failure
(CRF) not yet on dialysis. Herein, we report a case of fatal
Al-related encephalopathy in a patient with severe CRF,
not on dialysis, due to the intake of large doses of antacids
containing Al for at least 3 years.
Case. A 59-year-old white male patient with CRF due
to diabetic nephropathy was followed as an out-patient in
our chronic kidney disease clinic. When he was 47 years
old, diabetes mellitus was diagnosed, and he was treated with
oral antidiabetics for 2 years and thereafter with insulin.
At 55, a severe polyneuropathy and distal occlusive arterial
disease with foot gangrene occurred that required the
amputation of the left foot. He suffered from gastric pain
which he self-treated with Al hydroxide (MaaloxÕ TC).
A gastroduodenoscopy was performed that revealed antral
gastritis positive for Helicobacter pylori. Despite the anti-
biotic treatment, the patient continued taking Al hydroxide.
From the age of 57, he regularly attended our chronic kidney
disease clinic. His serum creatinine was between 3 and 4 mg/dl
2930
and his BUN between 75 and 85 mg/dl. At the age of 59,
during a visit, the nephrologists noticed speech disturbances,
mostly stuttering. A cerebral computed tomography (CT)
scan was performed, which was normal. He had a hypochro-
mic anaemia (Hb ¼ 9.2 mg/dl, MCV ¼ 65 fl), severe CRF
(creatinine ¼ 5.4 mg/dl), hyperkalaemia (6 mEq/l) and a
normal serum Ca (4.7 mEq/l). Haemodialysis was started.
On admission, the patient appeared malnourished. The
neurological examination showed disorientation, sponta-
neous tremor and no sign of meningeal irritation. All other
neurological tests were within normal limits. After a few
dialysis sessions, the patient became confused and lethargic.
The CT scan was repeated, but it was again unremarkable.
The electroencephalogram showed wide y and y-d waves,
often in a triphasic fashion, and diffuse slow spikes. Serum Al
was checked and found to be 740 mg/l. After a dialysis session,
the patient fell and fractured a femur. He was treated with
500 mg of desferrioxamine/day intramuscularly (Novartis,
Origgio, Italy) in 250 ml of physiological solution daily, for
1 month until death, but the neurological disturbances
progressed steadily. Repeated general seizures occurred,
and the patient died of a cardiogenic shock during a general
convulsion.
At autopsy, the brain weighed 1280 g, it was slightly
atrophic and no focal lesions were found. On light micros-
copicy, the grey matter presented spongiosis, cortical gliosis
and neuronal atrophy. Slight gliosis was present in the basal
nuclei; neuronal thickening was observed in the pons. Silver
staining of paraffin slides revealed argyrophilic deposits
in epithelia of choroid plexus, the cytoplasm of glial cells
and different neuronal populations of brainstem, cortex
and subcortical grey matter. Al concentrations (mg/g fresh
tissue) were 2.46 in the frontal lobe, 3.56 in the parietal
lobe, 2.34 in the temporal lobe, 2.89 in the cerebellum, 15.5
in the kidney, 20.3 in bone and 6.5 in the heart.
Comment. This case showed all three syndromes related
to Al toxicity, namely encephalopathy, bone disease and
microcytic anaemia. The total amount of ingested aluminum
was at least 3 kg in 3 years. He did not have end-stage renal
disease when he started taking Al hydroxide, but moderate
to severe renal failure with a serum creatinine between 3 and
4 mg/dl.
Most reported cases refer to patients on peritoneal
dialysis or haemodialysis. Only a few have been described
in patients not yet on dialysis: a patient who developed
Al-related bone disease after the ingestion of 711 g in
1 year [2]; a child with microcytosis due to high Al doses
given to treat hyperphosphataemia [3]; and two patients
with dialysis encephalopathy syndrome due in one case
to the use of Al-containing phosphate binders for 2 years,
and in the other to the concommitant intake of citrate
[4]. Four other CRF patients took Al hydroxide and
citrate together and developed encephalopathy [5]. Finally,
a case of osteomalacia due to prolonged antacid use
was reported in a patient with normal renal function [6].
The peculiarity of the present case is the presence of
the complete picture of Al toxicity and the exceedingly high
levels of serum Al.
The kinetics of Al absorption in CRF were well described
by Sárszegi et al. [7]. In patients with moderate CRF, serum
Al concentration was twice as high as baseline, even 24 h after
the administration of a compound containing 58.1 mg of Al.
The most interesting finding was that CRF patients were
unable to excrete Al as compared with healthy subjects,
i.e. the problem was not absorption, but excretion. Moreover,
Al kinetics were the same in patients with moderate and
severe CRF.
Nephrol Dial Transplant (2004) 19: 2930
Although sufficient evidence exists to show that some
degree of Al overload occurs in Al-treated patients even
in the presence of normal renal function, the problem
arises with long-term treatments with Al-containing
compounds. This was the case in our patient and in the
other patients alluded to above [2–6]. The occurrence of Al
intoxication is so rare at present that it no longer seems
to be a problem. However, because we do not know the
prevalence of the use of Al compounds in CRF patients,
the symptoms of mild forms of intoxication may be easily
missed. As a matter of fact, the cases described in the
literature are very severe. Not much is known about the
effects of low-dose long-term exposure, or whether it
may contribute to patient morbidity and mortality in the
long run.
It is well known that Al-containing compounds should
be avoided in CRF patients, that care should be taken
in limiting their use to the short-term reduction of high
serum phosphate, and that all possible alternatives should
be considered. However, sometimes, as in our case, the
patient self-prescribes the drug. In this situation, only
regular monitoring can detect patients at risk of Al
intoxication.
Conflict of interest statement. None declared.
1
CNR-Institute for Biomedical Technologies Paolo Zatta1
Metalloproteins Unit Pamela Zambenedetti2
Department of Biology Erich Reusche3
University of Padova Florian Stellmacher3
Vialle G. Colombo 3 Alberto Cester4
35121 Padova Paolo Albanese4
2
Pathology Division and Gina Meneghel5
Brain Bank Maurizio Nordio6
4
Geriatric Division
5
Nephrology and Dialysis Unit
General Hospital ULS 513
Dolo-Venice
6
Nephrology and Dialysis Unit
SS Giovanni e Paolo Hospital ULSS 12,
Venezia, Italy
3
Institute for Pathology/Neuropathology
Medical School
Luebeck, Germany
Email: zatta@mail.bio.unipd.it
1. Wills MR, Savory J. Aluminum and chronic renal failure:
sources, absorption, transport, and toxicity. Crit Rev Clin Lab
Sci 1989; 27: 59–107
2. Kaye M. Oral aluminum toxicity in a non-dialyzed patient with
renal failure. Clin Nephrol 1983; 20: 208–211
3. Shah NR, Oberkircher OR, Lobel JS. Aluminium-induced
microcytosis in a child with moderate renal insufficiency. Am J
Pediatr Hematol Oncol 1990; 12: 77–79
4. Russo LS, Beale G, Sandroni S, Ballinger WE. Aluminium
intoxication in undialysed adults with chronic renal failure.
J Neurol Neurosurg Psychiatry 1992; 55: 697–700
5. Woodson GC. An interesting case of osteomalacia due to
antacid use associated with stainable bone aluminium in a
patient with normal renal function. Bone 1998; 22: 695–698
6. Bakir AA, Hryhorczuk DO, Ahmed S et al. Hyperaluminemia
in renal failure: the influence of age and citrate intake. Clin
Nephrol 1989; 31: 40–44
Nephrol Dial Transplant (2004) 19: 2931
7. Sárszegi Z, Nagy J, Jobst K. The kinetics of initial gastro-
intestinal absorption of an aluminium-containing antacid
(Tisacid) in patients with various stages of chronic renal
insufficiency. Nephrol Dial Transplant 1997; 12: 372–373
doi:10.1093/ndt/gfh439
Sirolimus-induced pneumonitis, sinusitis
and macular oedema
Sir,
Sirolimus is being used increasingly in calcineurin inhibitor-
free regimens in solid organ transplant immunosuppression
[1,2]. However, it has potential pulmonary toxicity due to
a capillary leak syndrome [3,4]. We report for the first time
one such case with involvement of the paranasal sinuses
and retina in addition to sirolimus-induced pneumonitis, all
probably related to the same underlying pathophysiology.
A 54-year-old male with presumed chronic tubulointer-
stitial nephritis and end-stage renal disease (ESRD) on inter-
mittent haemodialysis treatment underwent cadaver renal
transplantation in August 2003. He was given daclizumab
induction, followed by mycophenolate mofetil (MMF)
1000 mg per day and sirolimus (6 mg loading followed by
2 mg once daily) and low dose prednisolone as immuno-
suppression. Cyclosporin was avoided due to delayed graft
function. MMF was withdrawn and cyclosporin (3 mg/kg)
was introduced after 2 weeks once adequate graft func-
tion was established. His baseline serum creatinine at this
time was 1.8 mg/dl. One month post-transplant, he was
found to have diabetes mellitus for which he was put on
insulin therapy. Two months post-transplant, he presented
with complaints of increasing breathlessness and headache.
He was afebrile, normotensive and had no systemic oedema.
Chest examination revealed bilateral crepitations. Fundos-
copy showed bilateral macular oedema. Blood chemistry
showed a haemoglobin of 11.2 g/dl, TLC 11 300/mm3, serum
urea 83 mg/dl and creatinine 1.8 mg/dl. Chest X-ray showed
bilateral non-homogeneous opacities in the middle and lower
zones, and X-ray of the paranasal sinuses revealed bilateral
opaque maxillary sinuses and hazy frontal sinuses. Computed
tomography (CT) scan showed mucosal oedema and thicken-
ing of all the sinuses (frontal, ethmoid, sphenoid and
maxillary). Sputum cultures were sterile. Fluorescein fundus
angiography showed pooling of contrast suggestive of central
serous retinopathy.
Sirolimus was stopped and he was managed conservatively
without antibiotics as there was no evidence of infection.
A sirolimus trough level was not done as we did not have the
facility at our centre. Bronchial alveolar lavage was not done
due to rapid resolution of symptoms. His breathlessness
and headache subsided during the next 48 h. At repeat X-rays
of chest and paranasal sinuses, the initial findings were almost
cleared up and at fundus examination a decreased macular
oedema was found.
There have been several case reports of pneumopathy
with the usage of sirolimus [3–5]. None of them have reported
involvement of paranasal sinuses and the retina, probably
because this was not looked for in view of the dominant
pulmonary symptomatology. Case reports mention high
drug levels, graft dysfunction and hypervolaemia to be
possible risk factors [2,3].
This case reminds us of the importance of identification
of potential toxicities of the immunosuppressive regimens,
e.g. sirolimus. The acute toxic effects as a rule are reversible,
2931
and cessation of the drug usually leads to resolution of the
side effects.
Conflict of interest statement. None declared.
Global Hospital Shivanand Karopadi Nayak
Nephrology Department Tarun K. Jeloka
Hyderabad, AP Subhramanyam V. Sreepada
India
Email: nayak@pol.net.in
1. Groth CG, Backman L, Morales JM et al. Sirolimus
(rapamycin)-based therapy in human renal transplantation:
similar efficacy and different toxicity compared with cyclosporin.
Transplantation 1999; 67: 1036–1042
2. Morelon E, Mamzer-Bruneel MF, Peraldi MN et al. Sirolimus:
a new promising immunosuppressive drug. Towards a rationale
for its use in renal transplantation. Nephrol Dial Transplant
2001; 16: 18–20
3. Morelon E, Stern H, Kreis H. Interstitial pneumonitis
associated with sirolimus therapy in renal transplant recipients.
N Engl J Med 2000; 343: 225–226
4. Singer SJ, Tiernan R, Sullivan EJ et al. Interstitial pneumonitis
associated with sirolimus therapy in renal transplant recipients.
N Engl J Med 2000; 343: 1815–1816
5. Mahalati K, Murphy DM, West ML. Bronchiolitis obliterans
and organizing pneumonia in renal transplant recipients. Trans-
plantation 2000; 69: 1531–1532
6. Kaplan MJ, Ellis CN, Csorgo ZB et al. Systemic toxicity
following administration of sirolimus (formerly rapamycin) for
psoriasis. Arch Dermatol 1999; 135: 553–557
7. Haydar Ali A, Denton M, West A, Rees J, Goldsmith DJA.
Sirolimus-induced pneumonitis: three cases and a review of the
literature. Am J Transplant 2004; 4: 137–139
doi:10.1093/ndt/gfh465
Old-time features are back in renal transplanted
patients
Sir,
Uraemic stomatitis is a very rare oral mucosal disorder
possibly because nowadays patients are seldom left without
dialysis at advanced and prolonged stages of renal failure.
The present report details the features of uraemic stomatitis in
a patient with longstanding chronic renal failure.
A 46-year-old male was referred by the nephrology
department of Hospital das Clinicas to the oral medicine
unit of UFPE, Recife, Brazil, complaining of a burning
sensation of the oral mucosa and dysgeusia. The patient had
developed chronic renal disease due to non-specific nephritis
associated with severe hypertension in 1991, at which time
he commenced haemodialysis. In the same year the patient
underwent renal transplantation but the renal allograft was
rejected 4 years later. The patient continued haemodialysis
for 10 years until he underwent a further renal transplant in
2001. Perhaps surprisingly, at the time of referral his renal
disease was considered stable, aside from elevation of plasma
urea (288 mg/ml: normal range 18–21 mg/ml) and creatinine.
Unfortunately, no details of calcium, phosphate or haemo-
globin were available at that time. Intra-oral examination