Department of Nephrology and 1 Department of Pathology, Hospital Timone, Marseille, France 2 Department of Medicine, Hospital Conception, Marseille France
Correspondence and offprint requests to: Dr H. Vacher-Coponat, Department of Nephrology, Hospital Conception, Marseille, France.
Keywords: chronic myelocytic leukaemia; interferon; renal failure; thrombotic microangiopathy
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Introduction |
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We observed a patient with chronic myelocytic leukaemia (CML) who was treated with -IFN for 10 years and developed thrombotic microangiopathy with neurological, cardiac and renal manifestations. The neurological and cardiac manifestations regressed when
-IFN was stopped, but the renal disease progressed to ESRF necessitating chronic haemodialysis.
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Case |
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She suffered from CML and had been treated with -IFN and hydroxyurea for 10 years. Three months prior to hospitalization, she had developed a skin ulcer related to hydroxyurea. Hydroxyurea was discontinued and treatment with pipobroman was initiated.
One week prior to hospitalization, she was treated with amoxicillin and ciprofloxacin for a flu-like syndrome with cardiac pain and dyspnoea.
On admission, the patient was in poor health. Her level of consciousness fluctuated. She had no fever, and her blood pressure was normal. Serum biochemical and haematological values were: 360 µmol/l serum creatinine; 67 g/l total protein; 31 g/l serum albumin; 13 000/mm3 white blood cells with 95% polyneutrophils; 7.4 g/dl haemoglobin; haematocrit 24%; 1 162 000/mm3 platelets; 685 IU/l lactic dehydrogenase (normal range 120350 UI/l); and 20 µmol/l total bilirubin (normal range 017 µmol/l). Urinalysis revealed: 1.5 g per day proteinuria, 500/mm3 red blood cells, and no white blood cells.
The electroencephalogram showed severe non-specific changes. Lumbar puncture and cerebral scan were normal. An echocardiogram showed massive pericardial effusion and severe diffuse hypokinesia of the left ventricle (ejection fraction=20%). Pericardial puncture yielded a transudate.
Interferon and pipobroman were discontinued. A rapid rise in white blood cells was treated with hydroxyurea. Renal function deteriorated progressively and haemodialysis was initiated 3 weeks later. Percutaneous renal biopsy was performed. Light microscopy revealed that two out of eight glomeruli were obsolescent, three showed signs of ischaemia, and subendothelial swelling was seen in the remaining three glomeruli. Thickening of arteriolar walls, arteriolar thrombi and interstitial fibrosis were noted (Figure 1). Immunofluorescence showed IgM and C3 staining in vessel walls, and IgM staining in the subendothelial space. A diagnosis of haemolyticuraemic syndrome was made. At this time, fragmented red blood cells were not demonstrable and haptoglobin concentration was normal. Tests for ANF, ANCA, RF, antiphospholipid antibodies, cryoglobulin, cytomegalovirus, EpsteinBarr virus, hepatitis B and C virus, and human immunodeficiency virus were negative. Blood and urine cultures were negative.
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Discussion |
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A role for -IFN treatment in the development of thrombotic microangiopathy is possible. The absence of other evident causes and the homogeneity of all
-IFN-related thrombotic microangiopathy suggests a link between
-IFN and thrombotic microangiopathy. All reported patients had leukaemia (usually CML) and the treatment with
-IFN was initiated many months before thrombotic microangiopathy occurred. ESRF frequently occurred. The mechanisms by which
-IFN induces endothelial injury have not been clarified. However, an immune mechanism is probably involved. IFN enhances cellular immunity and increases expression of endothelial cell HLA antigens [9].
-IFN induces production of autoantibodies, and anti-endothelial antibodies have been described in patients with thrombotic microangiopathy [10,11]. Moreover, thrombotic microangiopathy can be induced by antiphospholipids which have been reported in patients treated with
-IFN [12].
The prominence of thrombotic microangiopathy patients with CML treated by long-term -IFN suggest that these two factors may play a role in the development of thrombotic microangiopathy. Immunological disorders, characteristic of CML, neutrophil proliferation and thrombocytosis, may favour
-IFN toxicity. CML as the sole cause of thrombotic microangiopathy seems unlikely. Indeed, CML has been recognized for >90 years, but thrombotic microangiopathy in CML patient has only recently been reported, and always in association with
-IFN treatment [13].
Diagnosis of thrombotic microangiopathy can be difficult in patients with CML. Indeed, thrombocytopenia can be absent, elevated lactate dehydrogenase (LDH) levels are common in CML and anaemia is also usual in CML.
Renal prognosis in thrombotic microangiopathy due to -IFN is poor. Six out of the eight patients reported in the literature developed ESRF and were on dialysis [37]. The remaining two patients suffered from persistent renal failure but were not treated with dialysis. Patient survival is generally poor and correlated with the progression of the CML or with the severity of the thrombotic microangiopathy. Since only a few cases have been reported, it is difficult to evaluate the efficacy of specific therapy for thrombotic microangiopathy.
In conclusion, renal failure is a rare event with -IFN treatment. In CML patients, after many months of treatment with
-IFN, thrombotic microangiopathy can occur and requires discontinuation of
-IFN and histological confirmation. Perhaps earlier treatment can modify the poor evolution of thrombotic microangiopathy.
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References |
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