Nephrogenic Diabetes Insipidus Following High Dose Epirubicin Chemotherapy for Metastatic Soft Tissue Sarcoma [Letter]

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Title: Nephrogenic Diabetes Insipidus Following High Dose Epirubicin Chemotherapy for Metastatic Soft Tissue Sarcoma [Letter]
Authors: Vasey, P.A.; Dunlop, D.J.; Steward, W.P.
Publisher: European Journal of Cancer
Date Published: 1995
Reference Number: 79
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Abstract • Article • Translation
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Reprinted from European Journal of Cancer, Vol 31A, No 1, P.A. Vasey, D.J. Dunlop and W.P. Steward, "Nephrogenic Diabetes Insipidus Following High Dose Epirubicin Chemotherapy for Metastatic Soft Tissue Sarcoma", p. 126, 1995, with permission from Elsevier Science. No part of this article may be reproduced in any way without permission in writing from the publisher.

Figure 1  Results of water deprivation test showing failure to concentrate the urine in response to DDAVP. The patient achieved a 4 h post DDAVP urine osmolarity of 27% greater than the baseline value, and as such fulfils [sic] the diagnostic criteria for nephrogenic DI.
A 52 year old woman presented with an extensive pelvic recurrence of a low grade neural sarcoma which had been completely excised 2 years previously. There were also multiple pulmonary metastases and, apart from mild dyspnoea on exertion, there were no other specific symptoms. Her ECOG performance status was 1. Routine haematological and biochemical investigations were normal, and chemotherapy was started with high dose epirubicin 150 mg/m2 intravenously (i.v.) three times a week (with ondansetron 8 mg i.v. and dexamethasone 8 mg i.v. as an antiemetic prophylaxis) as part of a clinical trial. Following this, she experienced vomiting and diarrhoea, but also increasing thirst and polyuria. She developed myelosuppression (neutrophil nadir 0.51 x 109/l), but serum biochemical analysis revealed no significant abnormalities (potassium 4.1 mmol/l, urea 3.3 mmol/l, serum creatinine 60 ?mol and corrected calcium 2.22 nmol/l). A 24 h urine creatine clearance was 60 ml/min. Urinalysis revealed pus cells, but no organism was grown from any of the cultures. She subsequently received two further cycles, and continued to complain of polydipsia and polyuria. Abdominal ultrasound demonstrated mild hydronephrosis on the right plus slight dilatation of the left calyceal system. Creatinine clearance had risen to 92 ml/min, urea 9.3 mmol/l, sodium 142 mmol/l, potassium 4.2 mmol/l, creatinine 149 ?mol/l and calcium 2.5 mmol/l. The rest of her routine biochemistry parameters were normal. Plasma osmolality was 296 mmol/kg (normal range 275-295), urine osmolality 191 mmol/kg, thyroxine 106 nmol/l and thyroid-stimulating hormone (TSH) 3.92 mU/l indicated a euthyroid state. Serum cortisol at 9 a.m. was 564 nmol/l and parathyroid hormone (PTH) was 3.3 pmol/l (both within normal ranges). A standard water deprivation test was carried out which suggested the diagnosis of nephrogenic diabetes insipidus (Figure 1). A brain C.T. scan showed no evidence of intracerebral metastatic disease, or ventricular enlargement. Ultrasound now revealed moderate bilateral hydronephrosis secondary to pelvic disease, measuring 12 cm x 13 cm x 12 cm. Despite this, renal function remained adequate, with urea 7.7 mmol/l creatinine 125 ?mol/l, and creatinine clearance 56 ml/min. The patient had subjective improvement after intranasal deamino-D-arginine vasopressin (DDAVP), and this was administered at 20 ?g, three times daily. Unfortunately, her disease continued to progress and despite further care, she died 6 weeks later.

Nephrogenic diabetes insipidus (NDI) occurs when there is insensitivity of the renal collecting tubules to the phsyiological [sic] effects of antidiuretic hormone (ADH). Drug-induced NDI has been increasingly recognised [sic] over the years (for review see Singer and Forrest [1]) although there is little evidence implicating cytotoxic drugs in the aetiology of this syndrome [2-5]. There has been no reported correlation with electrolyte disturbance or endocrine abnormality either at standard or high doses of epirubicin, and non-haematological toxicities such as nausea, vomiting, diarrhoea [sic] and stomatitis have generally showed a lack of correlation with dose [6-10]. There is a clear temporal relationship between the administration of epirubicin and the onset of polyuria and polydipsia in this particular patient, and the lack of significant renal impairment at the onset of symptoms and the mild degree of the hydronephrosis make obstructive nephropathy an unlikely cause (although it may have contributed to it in the later stages). Although we feel that an idiosyncratic response to epirubicin is the likely cause, there is the possibility that the combination of mild hydronephrosis and high dose epirubicin has had additive or synergistic effects on the ADH/water clearance mechanisms to such an extent that clinical nephrogenic DI occurred.

REFERENCES
  1. Singer I, Forrest JN. Drug-induced states of nephrogenic diabetes insipidus. Kidney Int 1976, 10, 82-95.
  2. DeFronzo RA, Braine H, Colvin OM, Davis PJ. Water intoxication in man after cyclophosphamide therapy: time course and relationship to drug activation. Ann Int Med 1973, 78, 861-869.
  3. DeFronzo RA, Abeloff M, Braine H, Humphrey RL, Davis PJ. Renal dysfunction after treatment with isophosphamide (NSC-109724). Cancer Chemother Rep 1974, 58, 375-382.
  4. Dousa TP, Barnes LD. Effect of colchicine and vinblastine on the cellular action of vasopressin in mammalian kidney. J Clin Invest 1974, 54, 252-262.
  5. Focan C, Boossy J, Focan-Henrard D, et al. Phase II trial with high dose ifosfamide and mesna given in a 24-h infusion for advanced GI tract cancer. Cancer Chemother Pharmacol 1989, 23, 192-193.
  6. Holdener EE, Jungi WJ, Fiebig HH, et al. Phase I study of high-dose epirubicin in non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1988, 7 208.
  7. Karp D, Colajori E, Karpovsky B, et al. A phase I trial of high dose epirubicin (EPI) in advanced cancer. Proc Am Soc Clin Oncol 1989, 8 83.
  8. Tjuljandin SA, Doig RG, Sobol MM, et al. Pharmacokinetics and toxicity of two schedules of high dose epirubicin. Cancer Res 1990, 50, 5095-5101.
  9. Casazza AM, DiMarco A, Bertazzoli C. Antitumour activity, toxicity and pharmacological properties of 4'-epi-adriamycin. In Siegenthaler A, Luthy R, (eds). Current Chemotherapy, Vol 2. American Society of Microbiology, Washington, 1978, 1257-1260.
  10. Cersosimo RJ, Hong WK. Epirubicin: a review of the pharmacology, clinical activity and adverse effects of an adriamycin analogue. J Clin Oncol 1986, 4, 425-439.

Beatson Oncology Centre, Western Infirmary, Glasgow, G11 6NT, U.K. (P.A. Vasey, D.J. Dunlop and W.P. Steward)

Revised 9 Aug. 1994; accepted 29 Sep. 1994.

Address correspondence and reprint requests to Elsevier Science, Permissions Dept., The Bouvlevard, Langford Lane, Kidlington, Oxford 0X5 1GB, UK

This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)

A 52-year-old woman whose cancer was spreading to her lungs was treated with high doses of the drug epirubicin. She experienced several side effects such as vomiting and diarrhea, but also polyuria (chronic, excessive urination) and polydipsia (chronic, excessive thirst). She was continued on the epirubicin and continued to experience polydipsia and polyuria. Ultrasound revealed only a mild distention of the kidney caused by urine. A standard water deprivation test was carried out which indicated she had nephrogenic diabetes insipidus (NDI). She was treated with a synthetic vasopressin (DDAVP), and reported that she felt better. Unfortunately, after six more weeks of treatment, she died.

That certain drugs can induce NDI is becoming more well known, though there is little evidence implicating drugs such as epirubicin. However, there was a clear relationship between the administration of epirubicin and the onset of NDI in this patient. The authors think that this woman's NDI was caused by an idiosyncratic response to the drug on the part of the woman, though the combination of the mild kidney distention and high dose of epirubicin might have had an additive or synergistic effect on the antidiuretic hormone water clearance mechanisms to such an extent that clinical NDI occurred.