Internal Medicine, Departments of Pathology, Franz Volhard Clinic, Klinikum Buch, Medical Faculty of the Charité, Humboldt University of Berlin, Germany
Sir,
Haemolytic uremic syndrome (HUS) is a well described complication of antineoplastic chemotherapy [1]. Gemcitabine (2',2'-difluordeoxycytidine, dF-dC) is a novel pyrimidine antimetabolite with a broad spectrum of antitumour activity [2]. The drug has generated enthusiasm in the treatment of advanced adenocarcinoma of the pancreas because of good tolerance and relatively few side effects [3]. However, recently HUS have been reported in association with the use of gemcitabine. A mild HUS appeared to result from gemcitabine therapy in a patient with pancreatic carcinoma [3]. HUS was described in three other patients after prolonged treatment [4]. Brodowicz et al. observed a patient with HUS after gemcitabine therapy who developed dialysis-dependent chronic renal failure despite immediate treatment with prednisolone and plasmapheresis [5]. Dose dependency, duration of treatment, and prognosis of acute renal failure following gemcitabine have not been established. We have seen a case of biopsy-proven HUS requiring maintenance haemodialysis in a 51-year-old man who was treated with gemcitabine because of advanced pancreatic carcinoma.
Case.
A 51-year-old man underwent a Whipple operation after carcinoma of the pancreas was detected. The tumour and four involved lymph nodes were removed, after which the patient was treated with 5-fluorouracil and irradiation. Eight months later, three hepatic metastases were detected and gemcitabine (1900 mg/m2) was administered intravenously weekly for three consecutive weeks, followed by one week's rest, every four weeks. Therapy was stopped after seven cycles; the hepatic metastases were reduced in size. Two months later, the patient presented with dyspnea and pitting oedema. He was dyspneic and hypertensive, but afebrile. Physical examination revealed fine crackles over both lungs, an apical systolic murmur, and pitting oedema of both legs. Chest Roentgenogram showed bilateral perihilar infiltrates. Serum creatinine which had been normal before gemcitabine treatment, was 7.8 mg/dl, haemoglobin was 8 g/dl, haematocrit 26 vol%, haptoglobin concentration was reduced, indirect bilirubin and LDH were elevated, and reticulocyte count was 7.9%. The urine revealed mild proteinuria and was positive for blood. Microscopically, a few erythrocytes and granular casts were identified. A 24 h collection revealed 1.36 g protein and a creatinine clearance of 5 ml/min. A friction rub was then identified and haemodialysis was begun. The renal biopsy is shown in Figure 1. Prominent features are microthrombi and fibrinoid necrosis in small vessels and focal haemorrhage. The renal function never recovered and the patient died of metastatic pancreatic carcinoma 8 weeks later.
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HUS is a group of uncommon disorders with overlapping clinical findings characterized by microangiopathic haemolytic anaemia, thrombocytopenia, and varying degrees of renal failure [6]. Occlusion of arteries and arterioles by platelets and fibrin thrombi is important for the clinical manifestations of the disorder, as our renal biopsy typically indicated. Conventional causes are diarrhoeal diseases most prominently those related to Esherichia coli O157:H7, malignant hypertension, malignancy, pregnancy, autoimmunity, HIV infection, and hereditary factors. Medication-induced HUS is particularly important because of its iatrogenic nature and the opportunity for avoidance. Numerous drugs and toxins are implicated, including immunosuppressive agents notably cyclosporin and tacrolimus, antineoplastic agents particularly mitomycin C, adriamycin, cisplatin, deoxycoformycin, and alpha-interferon and relatively common drugs such as ticlopidine and quinine. Gemcitabine, a new pyrimidine analogue has recently been added to the list. A dose or duration effect has been difficult to establish. Our patient received seven cycles of treatment which could indicate a cumulative effect. Flombaum et al. [4] observed three patients who received the drug for a year. Their patients' renal function improved when the drug was stopped. We have little reason to believe that other than drug cessation and support, therapeutic measures alter the course of this complication [7].
The mechanism of gemcitabine-induced HUS is unknown, although endothelial activation is likely to be involved [8]. To our knowledge, no one has attempted to produce an animal model of this particular drug-induced HUS. Such a model might give insight into the mechanisms involved. Internists, oncologists, and nephrologists must be aware of this possible complication. A wider application of the drug is likely to result in additional cases. Early attention to renal function and thrombocyte levels may offer an opportunity for prevention.
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