Nephrology and Dialysis Unit Hospital of Martina Franca Italy
Sir,
Methotrexate (MTX; molecular weight 454.4 kDa) is an antimetabolite of folic acid. About 35% of MTX is bound to plasma proteins and up to 90% of the absorbed amount is excreted in the urine unchanged within 48 h, mostly within the first 8 h (glomerular filtration and active tubular secretion) [1]. MTX is widely used in rheumathoid arthritis (RA) [2]. In patients affected by RA and with normal renal function, the recommended doses are within a range of 57.5 mg/week. This dose can be increased by steps of 25 mg, up to a maximal dose of 15 mg/week. The drug has proved to be remarkably effective, often within weeks of initiation [2]. However, several cases of life-threatening pancytopenia caused by low-dose MTX therapy in RA have been reported [36]. Gutierrez-Ureña et al. assessed the frequency of MTX-induced pancytopenia in RA through a MEDLINE literature search of 15 years (19801995) [6]. A total of 70 patients with pancytopenia related to MTX therapy were identified: 61 were described in published case reports, two from their own experience, and seven patients were from five long-term prospective studies. A total of 511 patients were included in the prospective trials, yielding an overall incidence of pancytopenia of 1.4% (seven of 511). Of the 70 cases reported, 12 patients died (17%). Most of them had impaired renal function, hypoalbuminaemia, concurrent infection, and/or concurrent medication with more than five drugs. The minimal cumulative MTX dose leading to fatal pancytopenia was 10 mg. The conclusions drawn by Gutierrez-Ureña et al. were that pancytopenia is not an uncommon side effect of low-dose pulse MTX therapy in RA. It can lead to serious complications, including death [6].
Very few cases of severe pancytopenia caused by low-dose MTX therapy, prescribed for the treatment of RA, have been reported in chronic uraemic patients on dialysis (to the best of our knowledge only three cases [35]). The first case was a 52-year-old woman who was prescribed a single oral dose of 2.5 mg MTX. She underwent severe neutropenia with concomitant pharingitis, oral ulcerations, and fever. Leucovorin and appropriate antibiotics were prescribed, and isolation techniques were started when bacteraemia was discovered. Charcoal haemoperfusion also was started. Eventually she died of cardiac arrest; at autopsy, a large subdiaphragmatic abscess was discovered [3]. The second case was a 57-year-old man who was prescribed a single oral dose of 5 mg MTX. He underwent severe pancytopenia with concomitant fever, severe stomatitis with multiple ulcers, and general fatigue. Granulocyte colony stimulating factor, transfusion of red blood cell and platelets, and appropriate antibiotics were prescribed. Plasmapheresis also was carried out. Eventually he recovered gradually [4]. The third case was a 60-year-old woman who was prescribed MTX at the weekly oral dose of 5 mg. Four days after the second administration, she developed pancytopenia with gastrointestinal disturbances (diarrhoea and buccal ulcerations). Calcium folinate was administered; the haemodialysis schedule was not modified and she continued with a high-flux membrane. Furthermore, she was placed in a sterile room for 1 week. Eventually she recovered within 3 weeks [5]. Furthermore, we report here a fourth case: the patient was a 74-year-old woman affected by renal amyloidosis secondary to RA. She had started haemodialysis treatment on February 6, 2001 and had been treated previously in another dialysis facility. MTX was prescribed because of insufficient effect of steroids on increased joint pain: 5 mg of MTX were administered orally 1 week apart (March 26 and April 2, 2001). Stomatitis with multiple ulcerations developed 6 days after the first dose of MTX (1 day before the second administration). On April 14, 2001 the patient had a fever of 38°C and on April 17, 2001 she was admitted to our nephrology ward. Laboratory findings at admission included severe pancytopenia: white blood cells (WBC) 1700/mm3 with 18% neutrophils, platelets 15000/mm3, haemoglobin 6.8 g/dl. She was treated with transfusion of red blood cells on 3 consecutive days (17, 18, and 19 April, 2001), one transfusion of platelets (April 18, 2001), appropriate antibiotics, rHuEPO, standard bicarbonate haemodialysis, and calcium folinate. On April 18, 2001 WBCs were 2300/mm3 with 14% neutrophils, platelets 8000/mm3, haemoglobin 6.9 g/dl; on April 23, 2001 WBCs were 8100/mm3 with 32% neutrophils, platelets 465000/mm3, haemoglobin 10.8 g/dl. She eventually recovered within 1 month.
Patients affected by chronic uraemia and treated by dialysis were not included in the five prospective trials examined by Gutierrez-Ureña et al. [6]; thus, we cannot know what is the overall incidence of pancytopenia in this specific class of patients. However, we guess that it must be much higher than 1.4%, because impaired renal function, hypoalbuminaemia, concurrent infection, and/or concurrent medication with more than five drugs, the risk factors for the development of pancytopenia reported as the most frequent by Gutierrez-Ureña et al. [6], may be present altogether in every single dialysis patient. Furthermore, the minimal single (not cumulative) MTX dose leading to fatal neutropenia in the cases reported in chronic uraemia was 2.5 mg [3].
MTX prescription is not recommended in patients with a creatinine clearance <10 ml/min [7]. We too recommend not prescribing MTX to dialysis patients, sharing the opinion expressed by Ellman et al. [3] and Nakamura et al. [4]. Our opinion is reinforced by the fact that serum MTX levels were measurable 12 days after a single oral dose of 2.5 mg, charcoal haemoperfusion treatment notwithstanding [3] and 20 days after a single oral dose of 5 mg, plasmapheresis treatment notwithstanding [4]. Actually, peritoneal dialysis, conventional haemodialysis, haemoperfusion, and plasmapheresis are reported to be ineffective in MTX intoxication [1]. In contrast, Wall et al., reporting an effective clearance of MTX using high-flux haemodialysis membranes of 92.1±10.3 ml/min, concluded that MTX therapy is a viable treatment option in patients with responsive malignancies despite the presence of renal failure [8]. However, we do maintain that MTX must not be used in dialysis patients, at least for the treatment of RA, because the toxicity of a drug is not only a matter of its clearance performed by a native or artificial kidney, but must take into account the clinical and biological tolerance of the patient as a whole.
Notes
Email: nefromartina{at}topvideo.net
References