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1
Paris Albert Bensman the recommended daily intake is only 5000 U. The associa-
France tion of vitamin A toxicity and hypercalcaemia is rare but
Email: tim.ulinski@trs.ap-hop-paris.fr 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
1. Shalev H, Romanovsky I, Knoers NV et al. Bladder function
because of activation of bone resorption by vitamin A [2].
impairment in aquaporin-2 defective nephrogenic diabetes
This man’s reduced baseline kidney function may have
insipidus. Nephrol Dial Transplant 2004; 19: 608–613
2. Ramsey EW, Morrin PA, Bruce AW. Nephrogenic diabetes
predisposed him to vitamin A toxicity. Given the modern
insipidus associated with massive hydronephrosis and bladder prevalence of use of alternative medicines and supple-
neck obstruction. J Urol 1974; 111: 225–228 ments, more such cases may occur, which emphasizes the
3. Tank ES, Alexander SR, Craven RM. Polyuric megalocystis. ongoing importance of vigilance and a careful medication
J Urol 1980; 124: 692–694 history.
4. Eika B, Levin RM, Longhurst PA. Comparison of urinary
bladder function in rats with hereditary diabetes insipidus,
Conflict of interest statement. None declared.
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- Department of Medicine Eric P. Cohen
ship to toilet training and frequency of micturition. Radiology Medical College of Wisconsin Chinmaya Trivedi
1993; 187: 803–806 Milwaukee
WI
doi:10.1093/ndt/gfh486 USA
Email: ecohen@mcw.edu
Hypercalcaemia from non-prescription vitamin A
1. Bergman SM, O’Malia J, Krane NK et al. Vitamin A induced
Sir, hypercalcemia: reponse to corticosteroids. Nephron 1988; 50:
Use of over-the-counter ‘natural’ supplements may have 362–364
unnatural effects. We report this case as a cautionary 2. Frame B, Jackson CE, Reynolds WA, Umphrey JE.
example. Hypercalcemia and skeletal effects in chronic hypervitaminosis
A 67-year-old white man was admitted to hospital in A. Ann Intern Med 1974; 80: 44–48
late January 2004, with malaise and hypercalcaemia. He
had undergone kidney transplantation 6 years earlier for doi:10.1093/ndt/gfh437
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- A fatal case of aluminium encephalopathy in a patient
chezia. His medications included prednisone, mycophenolate with severe chronic renal failure not on dialysis
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, Sir,
there was a tremor and unsteadiness of gait. The plasma Aluminum (Al) toxicity in patients with end-stage renal
creatinine was 450 mmol/l. The ionized calcium level was disease is a well known adverse effect due to either
1.7 mmol/l (normal 1.2–1.3). Intravenous normal saline was dialysate Al contamination or oral intake of Al-containing
given. Chest X-ray was normal. Upper and lower gastro- phosphate binders [1]. At present, the clinical forms of Al
intestinal endoscopy showed antral gastritis and two benign toxicity have almost disappeared. Al-containing drugs are
colonic polyps. Serum and urine protein electrophoresis given mainly as antacid agents and are often used without
did not show a paraprotein. The parathormone (PTH) level special caution in patients with chronic renal failure
was 17 pg/ml, (normal 10–65) and that of PTH-related (CRF) not yet on dialysis. Herein, we report a case of fatal
peptide was undetectable. The total plasma calcium reached Al-related encephalopathy in a patient with severe CRF,
2.5 mmol/l by hospital day 4. On that day, further enquiry not on dialysis, due to the intake of large doses of antacids
showed that he had been taking a dietary supplement containing Al for at least 3 years.
containing vitamin A, on the advice of an eye doctor, for Case. A 59-year-old white male patient with CRF due
the possible diagnosis of macular degeneration. This over- to diabetic nephropathy was followed as an out-patient in
the-counter supplement contains 7000 U of b-carotene our chronic kidney disease clinic. When he was 47 years
per tablet and he had been taking four tablets daily since old, diabetes mellitus was diagnosed, and he was treated with
the autumn of 2003. Because of the possibility of vitamin oral antidiabetics for 2 years and thereafter with insulin.
A-induced hypercalcaemia, this supplement was stopped At 55, a severe polyneuropathy and distal occlusive arterial
immediately. A retinol plasma level was 2550 mg/l (expected disease with foot gangrene occurred that required the
values 350–1200). A month later, he was feeling his usual self, amputation of the left foot. He suffered from gastric pain
the total plasma calcium had fallen to 2.4 mmol/l, and the which he self-treated with Al hydroxide (MaaloxÕ TC).
plasma creatinine had fallen to 400 mmol/l. A gastroduodenoscopy was performed that revealed antral
The increasing use of dietary supplements and over- gastritis positive for Helicobacter pylori. Despite the anti-
the-counter medicines, ‘natural’ or otherwise, may pose biotic treatment, the patient continued taking Al hydroxide.
significant risks. In this case, the total daily dose of vita- From the age of 57, he regularly attended our chronic kidney
min A that this patient was using was 28 000 U, whereas disease clinic. His serum creatinine was between 3 and 4 mg/dl
2930 Nephrol Dial Transplant (2004) 19: 2930
and his BUN between 75 and 85 mg/dl. At the age of 59, Although sufficient evidence exists to show that some
during a visit, the nephrologists noticed speech disturbances, degree of Al overload occurs in Al-treated patients even
mostly stuttering. A cerebral computed tomography (CT) in the presence of normal renal function, the problem
scan was performed, which was normal. He had a hypochro- arises with long-term treatments with Al-containing
mic anaemia (Hb ¼ 9.2 mg/dl, MCV ¼ 65 fl), severe CRF compounds. This was the case in our patient and in the
(creatinine ¼ 5.4 mg/dl), hyperkalaemia (6 mEq/l) and a other patients alluded to above [2–6]. The occurrence of Al
normal serum Ca (4.7 mEq/l). Haemodialysis was started. intoxication is so rare at present that it no longer seems
On admission, the patient appeared malnourished. The to be a problem. However, because we do not know the
neurological examination showed disorientation, sponta- prevalence of the use of Al compounds in CRF patients,
neous tremor and no sign of meningeal irritation. All other the symptoms of mild forms of intoxication may be easily
neurological tests were within normal limits. After a few missed. As a matter of fact, the cases described in the
dialysis sessions, the patient became confused and lethargic. literature are very severe. Not much is known about the
The CT scan was repeated, but it was again unremarkable. effects of low-dose long-term exposure, or whether it
The electroencephalogram showed wide y and y-d waves, may contribute to patient morbidity and mortality in the
often in a triphasic fashion, and diffuse slow spikes. Serum Al long run.
was checked and found to be 740 mg/l. After a dialysis session, It is well known that Al-containing compounds should
the patient fell and fractured a femur. He was treated with be avoided in CRF patients, that care should be taken
500 mg of desferrioxamine/day intramuscularly (Novartis, in limiting their use to the short-term reduction of high
Origgio, Italy) in 250 ml of physiological solution daily, for serum phosphate, and that all possible alternatives should
1 month until death, but the neurological disturbances be considered. However, sometimes, as in our case, the
progressed steadily. Repeated general seizures occurred, patient self-prescribes the drug. In this situation, only
and the patient died of a cardiogenic shock during a general regular monitoring can detect patients at risk of Al
convulsion. intoxication.
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 Conflict of interest statement. None declared.
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 1
in epithelia of choroid plexus, the cytoplasm of glial cells CNR-Institute for Biomedical Technologies Paolo Zatta1
and different neuronal populations of brainstem, cortex Metalloproteins Unit Pamela Zambenedetti2
and subcortical grey matter. Al concentrations (mg/g fresh Department of Biology Erich Reusche3
tissue) were 2.46 in the frontal lobe, 3.56 in the parietal University of Padova Florian Stellmacher3
lobe, 2.34 in the temporal lobe, 2.89 in the cerebellum, 15.5 Vialle G. Colombo 3 Alberto Cester4
in the kidney, 20.3 in bone and 6.5 in the heart. 35121 Padova Paolo Albanese4
2
Comment. This case showed all three syndromes related Pathology Division and Gina Meneghel5
to Al toxicity, namely encephalopathy, bone disease and Brain Bank Maurizio Nordio6
4
microcytic anaemia. The total amount of ingested aluminum Geriatric Division
5
was at least 3 kg in 3 years. He did not have end-stage renal Nephrology and Dialysis Unit
disease when he started taking Al hydroxide, but moderate General Hospital ULS 513
to severe renal failure with a serum creatinine between 3 and Dolo-Venice
6
4 mg/dl. Nephrology and Dialysis Unit
Most reported cases refer to patients on peritoneal SS Giovanni e Paolo Hospital ULSS 12,
dialysis or haemodialysis. Only a few have been described Venezia, Italy
3
in patients not yet on dialysis: a patient who developed Institute for Pathology/Neuropathology
Al-related bone disease after the ingestion of 711 g in Medical School
1 year [2]; a child with microcytosis due to high Al doses Luebeck, Germany
given to treat hyperphosphataemia [3]; and two patients Email: zatta@mail.bio.unipd.it
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 1. Wills MR, Savory J. Aluminum and chronic renal failure:
citrate together and developed encephalopathy [5]. Finally, sources, absorption, transport, and toxicity. Crit Rev Clin Lab
a case of osteomalacia due to prolonged antacid use Sci 1989; 27: 59–107
was reported in a patient with normal renal function [6]. 2. Kaye M. Oral aluminum toxicity in a non-dialyzed patient with
The peculiarity of the present case is the presence of renal failure. Clin Nephrol 1983; 20: 208–211
the complete picture of Al toxicity and the exceedingly high 3. Shah NR, Oberkircher OR, Lobel JS. Aluminium-induced
microcytosis in a child with moderate renal insufficiency. Am J
levels of serum Al.
Pediatr Hematol Oncol 1990; 12: 77–79
The kinetics of Al absorption in CRF were well described
4. Russo LS, Beale G, Sandroni S, Ballinger WE. Aluminium
by Sárszegi et al. [7]. In patients with moderate CRF, serum intoxication in undialysed adults with chronic renal failure.
Al concentration was twice as high as baseline, even 24 h after J Neurol Neurosurg Psychiatry 1992; 55: 697–700
the administration of a compound containing 58.1 mg of Al. 5. Woodson GC. An interesting case of osteomalacia due to
The most interesting finding was that CRF patients were antacid use associated with stainable bone aluminium in a
unable to excrete Al as compared with healthy subjects, patient with normal renal function. Bone 1998; 22: 695–698
i.e. the problem was not absorption, but excretion. Moreover, 6. Bakir AA, Hryhorczuk DO, Ahmed S et al. Hyperaluminemia
Al kinetics were the same in patients with moderate and in renal failure: the influence of age and citrate intake. Clin
severe CRF. Nephrol 1989; 31: 40–44
Nephrol Dial Transplant (2004) 19: 2931 2931
7. Sárszegi Z, Nagy J, Jobst K. The kinetics of initial gastro- and cessation of the drug usually leads to resolution of the
intestinal absorption of an aluminium-containing antacid side effects.
(Tisacid) in patients with various stages of chronic renal
insufficiency. Nephrol Dial Transplant 1997; 12: 372–373
Conflict of interest statement. None declared.
doi:10.1093/ndt/gfh439