Renal failure associated with a specific inhibitor of BCR-ABL tyrosine kinase, STI 571

Chagriya Kitiyakara and Vichai Atichartakarn1

Divisions of Nephrology and 1 Haematology, Faculty of Medicine, Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand Email: kitiyakc{at}yahoo.com

Sir,

Chronic myeloid leukaemia (CML) is a disorder in which cells of myeloid lineage undergo massive clonal expansion [1]. The characteristic abnormality of CML, the Philadelphia chromosome, results from a reciprocal translocation between chromosomes 9 and 22. The molecular consequence is the generation of BCR-ABL, a constitutively active tyrosine kinase, which is critical to the pathogenesis of the disease. Recently, an inhibitor of BCR-ABL, STI 571, has produced favourable responses in patients with CML, with relatively minor side effects [2,3]. Renal failure only occurred in one patient [2,3]. However, in these studies, other chemotherapeutic agents and patients with underlying chronic renal failure (CRF) were excluded. We report a case in which the use of STI 571 is associated with the development of acute on chronic renal failure.

Case.

In December 2000, a 67-year-old man was found to have an elevated white blood cell count (33.7x103/µl with left shift, and no blasts). Seven years earlier, he had had a heart transplant for ischaemic cardiomyopathy. In 1998, he was diagnosed with CRF, which was attributed to chronic cyclosporin toxicity. He also had symptomatic asthma, mild hypertension and hyperlipidaemia. His medications were: Neoral 100 mg bid, prednisolone 5 mg od, gemfibrozil 600 mg od, simvastatin 10 mg od, nifedipine CR 30 mg od, budesonide and terbutaline inhaler. The diagnosis of CML was made based on the presence of a hypercellular marrow with myeloid hyperplasia and BCR-ABL transposition. He was started on hydroxyurea with initial good response.

On April 10, 2001 (day 1), the patient was hospitalized for the treatment of a blastic transformation. On admission, he was euvolaemic with no peripheral oedema, with blood pressure (BP) 110/70 mmHg, which was similar to baseline. His laboratory values were: Hb 11.2 g/dl, white cell count 123x103/µl with 25% blasts, platelet 120x103/µl, urea 15.7 mmol/l, Cr 213 µmol/l, uric acid 630 µmol/l, glucose 6.1 mmol/l. Urinalysis: protein 1 positive, blood and glucose negative, red blood cells (RBC) 0/hpf, white blood cells (WBC) 1–2/hpf, with no casts. His serum creatinine and urinalysis were similar to baseline. Echocardiogram showed normal cardiac size and function.

The patient was started on allopurinol 300 mg od and given hydration. Nifedipine was stopped but otherwise he continued on his previous medications. On April 12 (day 3), he was given cytosine arabinoside (ARA-C) and started on STI 571 600 mg od (Figure 1Go).



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Fig. 1.  Time course and renal function.

 
From April 16 (day 7), his urine output decreased despite the use of frusemide, and he developed increasing oedema. He was afebrile and his BP remained stable throughout. On the April 18 (day 9), his laboratory values were: Hb 8.8 g/dl, WBC 49x103/µl with no blasts, urea 35 mmol/l, Cr 550 µmol/l, uric acid 666 µmol/l, Ca 1.83 mmol/l, Phos 2.66 mmol/l, Alb 3.0 g/dl, CPK 66 IU/l, normal liver function. Urinalysis: specific gravity 1:015, protein 1 positive, blood 3 positive, RBC 10–15, WBC 3–5 with no casts. His blood cyclosporin concentration was 150 ng/ml and was maintained at <250 ng/ml throughout his illness. Renal ultrasound showed normal sized kidneys with mild increase in echogenicity and no hydronephrosis, which was similar to previous studies. A diagnosis of acute on chronic renal failure was made. STI 571 was discontinued. His weight had increased by 10 kg and he developed pulmonary oedema with rising urea and creatinine. Haemodialysis was initiated and repeated on 4 consecutive days. During this time, his urine output had decreased to 330 ml per day.

From April 23 (day 14), his urine output improved in response to frusemide, and his creatinine began to fall on April 27 (day 18). His laboratory data were: urea 20 mmol/l, Cr 354 µmol/l, uric acid 258 µmol/l, Ca 1.86 mmol/l, Phos 1.97 mmol/l. At this time, a new emergence of blasts (WBC 60x103/µl, 49% blasts) was noted. ARA-C was given and STI 571 600 mg od was restarted. Over the next few days, he remained oedematous with mild pulmonary oedema despite increasing doses of frusemide. His serum creatinine, which was beginning to decrease, failed to fall further. By May 6 (day 27), the patient's urea had increased to 31 mmol/l and his creatinine increased. The patient remained haemodynamically stable and no evidence of new tumour lysis was seen. His urinalysis was similar to before the start of chemotherapy with no red or white blood cells. STI 571 was stopped again. Three days later, increasing diuresis was noted without changes in the diuretic dose. On May 12 (day 33), serum creatinine also started to decrease and urea decreased to 19.3 mmol/l. The patient's weight had also almost reached his baseline without the use of diuretics. Imipenem was started for increasing productive cough and mild fever, which resolved within a couple of days. On the May 14, blasts were detected again. Another dose of ARA-C was given and STI 571 was restarted at a lower dose of 300 mg od. Over the next few days, the patient's weight increased again despite increasing doses of diuretics. His urea and creatinine also increased. Urinalysis revealed no blood cells. STI 571 was stopped again but the patient's renal function continued to decline. Haemodialysis had to be initiated again. Two days later, he developed increasing cough and fever. Antibiotics were changed to cefoperazone/sulbactam and amphotericin B, but he remained febrile and dialysis-dependent. Again, there was recurrence of blasts. After discussion with his family, only symptomatic treatment was given. The patient died on May 31.

Comment.

This case raises the possibility that STI 571 may contribute to the development of renal failure, especially in patients with prior CRF or exposure to nephrotoxins. The exact kidney pathology is not known but acute tubular necrosis (ATN) is most likely. The initial renal injury could be explained by a combination of tumour lysis syndrome and STI 571, superimposed on chronic cycloclosporine nephrotoxicity. Tumour lysis is uncommon with STI 571 alone [2,3]. However, the combination with ARA-C and CRF might increase that risk. High serum phosphate and urine findings are consistent with tumour lysis syndrome. ARA-C is not widely known to cause renal failure. Large doses have been given to patients with CRF without precipitating ARF [4]. However, allergic interstitial nephritis has been reported in one case [5]. The role of STI 571 in the development of renal injury is unclear. The development and resolution of renal failure corresponds to the initiation and discontinuation of STI 571. The 600 mg dose of STI 571 causes oedema in up to 60% of patients with normal renal function, but this is usually mild [2,3]. Symptomatic oedema is likely to be more common and severe in patients with CRF and was a persistent problem in this case. Other factors including systemic infection and antibiotic use probably also contribute to the development of renal failure in the final instance.

STI 571 causes apoptosis in BCR-ABL-dependent leukaemic cells, but has a minimal effect on normal cells [1]. Indeed, the use of STI 571 is associated with only one case of renal failure in 141 treated cases with good baseline renal function [2,3]. However, the compound is not completely specific and also inhibits other kinases, including those associated with platelet-derived growth factor (PDGF) receptors, which may be important in renal tubular cell regeneration after ATN [1,6]. STI 571 can inhibit PDGF-dependent renal mesangial cell proliferation [7]. Thus STI 571 may interfere with PDGF receptor-mediated repair mechanisms in ATN. Alternatively, STI 571 also causes oedema, which may reflect increased capillary leakage. This could decrease effective circulating volume and renal blood flow, especially in patients with compromised cardiovascular, pulmonary and renal function.

In conclusion, STI 571 is a promising and relatively safe agent for the treatment of CML. The risk of nephrotoxicity appears to be small but limited data is available. This case raises the possibility that STI 571 may potentiate renal failure but further proof is needed. At present, caution may be necessary when this drug is used in the presence of renal failure or with other nephrotoxins.

References

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