Thalidomide for the nephrologist

Sir,

Thalidomide is used in a wide spectrum of diseases because of its antiangiogenic and immunological effects. It has now become one of the treatments of choice for myeloma. Since renal impairment is a frequent complication of myeloma, nephrologists will often have to prescribe this drug to their patients. Interest in thalidomide has also been reported in the treatment of uraemic pruritus.

Thalidomide undergoes plasma hydrolysis, the mechanism of which has not yet been clearly identified. A minor hepatic metabolism generates both active and non-active thalidomide metabolites [1]. However, those metabolites that have been identified in animal studies have not been recovered in humans, either in plasma or in urine [2,3]. Furthermore, thalidomide renal clearance is ~1.15 ml/min, whereas its total body clearance is 170 ml/min [3,4]. These data thus suggest that there is no need to adjust thalidomide dosage in patients with renal dysfunction.

However, thalidomide pharmacokinetics in patients with renal dysfunction have not been studied to date. In spite of this lack of data, this drug is often used in such patients. For example, Hayashi et al. recently reported the case of a patient on chronic haemodialysis receiving thalidomide 100 mg/day for the treatment of an immunoglobulin D multiple myeloma. During the first week of treatment, the patient developed constipation and peripheral neuropathy. Thalidomide dosage was thus reduced [5]. Furthermore, in eight patients with significant renal insufficiency who were receiving thalidomide 100–400 mg daily for refractory or relapsed myeloma, Harris et al. reported four cases of fatal hyperkalaemia (serum potassium, 7.5–9.1 mmol/l) [6]. The mechanism behind this apparent thalidomide-induced hyperkalaemia remains unclear. Therefore, the authors recommend caution when thalidomide is used in patients with moderate to severe renal failure (serum creatinine >300 µmol/l) or in patients on dialysis. To go a step further, we think that thalidomide should in all cases be started at a dosage that should not exceed 100 mg/day. It is also important to keep in mind that, even at this low dosage, thalidomide side effects may appear and that they may be severe.

Furthermore, thalidomide has been used to treat uraemic pruritus at a dosage of 100 mg/day in a study enrolling 210 patients with 29 cases of refractory uraemic pruritus in a crossover randomized double-blind trial with a 78% mean reduction in patients’ pruritus scoring. In this study by Silva et al., no side effect or biochemical abnormality has been reported [7].

Conflict of interest statement. None declared.

Hassane Izzedine, Vincent Launay-Vacher and Gilbert Deray

Department of Nephrology Pitié Salpêtrière Hospital Paris France Email: hassan.izzedine{at}psl.ap-hop-paris.fr

References

  1. Wood PMD, Proctor S. The potential use of thalidomide in the therapy of graft-versus-host disease. A review of clinical and laboratory information. Leukemia Res 1990; 14: 395–399[CrossRef][ISI][Medline]
  2. Czejka MJ, Koch HP. Determination of thalidomide and its major metabolites by high-performance liquid chromatography. J Chromatogr 1987; 413: 181–187[Medline]
  3. Chen TL, Vogelsang GB, Petty BG et al. Plasma pharmacokinetics and urinary excretion of thalidomide after oral dosing in healthy male volunteers. Drug Metab Dispos 1989; 17: 402[Abstract/Free Full Text]
  4. Gunzler V. Thalidomide in human immunodeficiency virus (HIV) patients: a review of safety considerations. Drugs 1992; 7: 116–134
  5. Hayashi T, Yamaguchi I, Saitoh H, Takagi M, Nonaka Y, Nomura T. Thalidomide treatment for immunoglobulin D multiple myeloma in a patient on chronic hemodialysis. Intern Med 2003; 42: 605–608[ISI][Medline]
  6. Harris E, Behrens J, Samson D, Rahemtulla A, Russell NH, Byrne JL. Use of thalidomide in patients with myeloma and renal failure may be associated with unexplained hyperkalaemia. Br J Haematol 2003; 122: 160–161[CrossRef][ISI][Medline]
  7. Silva SR, Viana PC, Lugon NV, Hoette M, Ruzany F, Lugon JR. Thalidomide for the treatment of uremic pruritus: a crossover randomized double-blind trial. Nephron 1994; 67: 270–273[ISI][Medline]




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