Renal thrombotic microangiopathy induced by interferon-{alpha}

Chérif Badid, Brigitte McGregor, J. Marie Faivre, Arnaud Guerard, Laurent Juillard, Denis Fouque and Maurice Laville

Service de Nephrology, Hôpital Edouard Herriot, Lyon, France

Keywords: acute renal failure; chronic myeloid leukaemia; interferon; thrombotic microangiopathy



   Introduction
 Top
 Introduction
 Case 1
 Case 2
 Discussion
 References
 
The interferons (IFN), are a family of glycoproteins with antiviral, antitumour and immunomodulatory activities. IFN-{alpha} is used particularly in the treatment of chronic myeloid leukaemia (CML) and other haematological malignancies, as well as in chronic hepatitis C. Various adverse effects associated with IFN-{alpha} have been reported previously, including cardiac and renal dysfunctions. Hypotension or tachycardia, and more severe cardiac complications such as arrhythmia and congestive heart failure have been reported and are usually reversible after IFN-{alpha} withdrawal [1]. In patients with chronic hepatitis C, IFN-{alpha} therapy is usually not associated with renal side effects. Conversely, in patients receiving high doses of IFN-{alpha} for malignancies, a wide range of renal side effects have been reported, including proteinuria (sometimes in nephrotic range), acute interstitial nephritis, and membranoproliferative glomerulonephritis [24]. In some cases, the discontinuation of treatment led to renal function resolution, but irreversible renal failure may occur [5]. Many authors have observed various renal toxicities with IFN-{alpha} therapy, but the incidence of renal complications remains unknown, and the causal link between IFN-{alpha} and thrombotic microangiopathy (TMA) is still underappreciated. We describe two cases of renal TMA in patients receiving IFN-{alpha} for CML. Hypotheses regarding the potential mechanisms underlying this association are discussed.



   Case 1
 Top
 Introduction
 Case 1
 Case 2
 Discussion
 References
 
CML was diagnosed in April 1987 in a 61-year-old male. The patient's leukocyte count was 308x109/l, platelet count was 440x109/l and renal function was normal (serum creatinine=92 µmol/l). He was initially treated with hydroxycarbamide (1 g/day), and 2 months later IFN-{alpha} (roferon) was added at a dose of 9x106 units three times per week. The dose of IFN-{alpha} was reduced in September 1987 to 6x106 units three times per week. In September 1989, bone marrow examination showed a partial remission and renal function was normal (serum creatinine 79 µmol/l). The patient was admitted to the emergency department in May 1991 for nausea, vomiting and headache. On admission he was pale, had high blood pressure (220/130 mmHg), but physical examination did not show major oedema. Cardiovascular, respiratory and abdominal examinations were normal. Fundoscopy detected a state III retinopathy. A cerebral tomodensitometry revealed multiple hypodensities. Blood biochemistry showed sodium 126 mmol/l (normal=135–145), potassium 4.2 mmol/l (normal=3.8–4.8), urea 24 mmol/l (normal=3–8), creatinine 562 µmol/l (normal=45–110) and proteinuria 2.8 g/24 h associated with microscopic haematuria. Renal ultrasound was normal. Haematological abnormalities were thrombocytopenia (98x109/l) and signs of intravascular haemolysis, including haemoglobin 9.1 g/dl and haptoglobin consumption <0.1 g/l, presence of numerous schistocytes, lactico-dehydrogenase (LDH) 1810 U/l (normal=210–450), unconjugated bilirubin 11.8 µmol/l (normal<2) and white blood cells 12.4x109/l. Rheumatoid factor, antinuclear antibodies, blood immune complex, anti-glomerular basement membrane antibodies and anti-neutrophil cytoplasmic antibodies were not detected. A coagulation screen gave normal results. After admission, antihypertensive drugs were administered (nicardipine and furosemide) and IFN-{alpha} therapy was withdrawn. Percutaneous renal biopsy disclosed typical signs of TMA. Eight plasma exchanges were performed and haemodialysis was done. The haematological abnormalities and LDH level returned to normal and renal function slowly improved. Thereafter, IFN-{alpha} treatment was withdrawn definitively, but hydroxycarbamide was maintained. Renal function improved and stabilized with a serum creatinine of 250 µmol/l. In December 1997 (6 years later), the patient died due to a blast crisis.



   Case 2
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 Introduction
 Case 1
 Case 2
 Discussion
 References
 
CML was diagnosed in February 1996 in a 54-year-old male who had a past history of hypertension that was well controlled with calcium channel blockers (nifedipine). Leukocyte count was 298x109/l and platelet count was 560x109/l. Combination treatment consisting of IFN-{alpha} (roferon) at a dose of 6x106 units three times per week and oral hydroxycarbamide at a dosage ranging from 1 to 2 g/day was started. Hydroxycarbamide was initially withdrawn after 3 months and then reintroduced again 9 months later, while IFN-{alpha} was continued at the same dosage. In April 1997, the leukocyte count was 11x109/l, the platelet count was 693x109/l, bone marrow examination showed a partial remission, and renal function was normal (serum creatinine 88 µmol/l). In January 1998, the patient was admitted to the cardiology department because of dyspnea and anasarca. Physical examination showed hypertension (185/100 mmHg) and pericarditis was rapidly diagnosed by echocardiography. Fundoscopy detected a stage II retinopathy. Renal dysfunction was noted (serum creatinine 289 µmol/l, urea 17.9 mmol/l) without abnormalities of renal ultrasound and continued to deteriorate rapidly. Leukocyte count was 5.4x109/l, platelet count was 220x109/l and signs of intravascular haemolysis included a haemoglobin level of 8.0 g/dl, haptoglobin consumption <0.08 g/l, the presence of some schistocytes, reticulocyte count 196x109/l, LDH level 1470 U/l, and unconjugated bilirubin 12 µmol/l. The coagulation tests only revealed an increased activated partial thromboplastin time (1.5 times compared with controls) without signs of disseminated intravascular coagulation: fibrinogen 5.5 g/l (normal=2–4), prothrombin time 79%. Urinalysis demonstrated microscopic haematuria and proteinuria (1.2 g/day). Searches for rheumatoid factor, antinuclear antibodies, anti-glomerular basement membrane antibodies and anti-neutrophil cytoplasmic antibodies were negative. Circulating immune complexes were found elevated at 13.2 µgEq/ml (normal<4). A pericardectomy was performed immediately, IFN-{alpha} therapy was withdrawn and haemodialysis was started secondarily. The patient developed neurological disorders and cerebral tomodensitometry revealed lacunas on periventricular area with a negative cerebrospinal fluid examination. Despite initiation of two plasma exchanges, the patient died rapidly of cardiac arrest during haemodialysis. A post-mortem percutaneous renal biopsy disclosed typical signs of TMA.



   Discussion
 Top
 Introduction
 Case 1
 Case 2
 Discussion
 References
 
The clinical presentations and laboratory findings are consistent with the diagnosis of haemolytic uraemic syndrome (HUS) renal dysfunction occurred with anaemia, and signs of haemolysis and the presence of schistocytes in the blood smear were detected. In the second case, thrombocytopenia was not observed, however the platelet count was reduced significantly in comparison with its usual level during follow-up. Thrombocytopenia is sometimes brief and therefore missed. Treatment with IFN-{alpha} was probably the only factor involved in the development of TMA. No other known causes could be suspected in our patients. HUS has already been reported during treatment with a number of cytotoxic agents (Mitomycin C, Cisplatin) but has never been described to date with hydroxyurea, suggesting a role for IFN-{alpha}. Moreover, in case 1, renal function and haematological abnormalities improved when hydroxyurea was continued. Interestingly, Creutzig et al. [6] compared the capillaroscopic findings during cooling in 25 patients treated with IFN-{alpha} with those of 10 healthy volunteers and observed occlusions of digital arteries, proven by hand arteriography, in cases of severe trophical lesions in some treated patients. The histological examination of an amputated finger revealed thrombotic occlusions of digital arteries and arterioles. All these observations support a causative relationship between IFN-{alpha} therapy and TMA. The delayed appearance of TMA observed in our report and others (Table 1Go) suggests that the development of renal lesions may be the result of cumulative effects. After reviewing the literature, we suggest that the development of late nephrotoxicity during IFN-{alpha} therapy is strongly predictive of renal TMA.


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Table 1. TMA associated with IFN-{alpha} therapy: a review of the literature

 
The mechanisms by which IFN-{alpha} could induce microangiopathic lesions remain unclear. An immune- mediated effect of IFN therapy is supported by experimental and clinical observations. Administration of IFN-{gamma} to newborn suckling mice leads to severe glomerulonephritis [7]. IFN-{alpha} has also been reported to induce the synthesis of autoantibodies. Some authors have suggested that antiphospholipid antibodies might be involved in the occurrence of renal TMA in patients treated with IFN-{alpha}, such as in antiphospholipid syn dromes with renal failure [8]. Unfortunately antiphospholipid antibodies were not tested, particularly in patient 2 who had abnormal coagulation tests. A direct action on endothelial cells is possible, similar to what has been observed in mice treated with IFN{alpha}/ß, who showed an active synthesis of glomerular basement membrane components (laminin, collagen IV) by endothelial cells [9].

Although the morbidity and mortality rates of TMA are declining, deaths and sequelae still occur (Table 1Go). The incidence of renal complications during IFN-{alpha} treatment remains unknown, but these additional cases are noteworthy as IFN-{alpha} is prescribed more often. The cases reported here suggest that close monitoring of renal function should be mandatory and continue indefinitely, particularly in patients on long-term IFN [10]. Discontinuation of IFN-{alpha} and renal biopsy should be considered immediately if early signs of renal dysfunction appear.



   Notes
 
Correspondence and offprint requests to: Dr C. Badid, Department of Nephrology, Edouard Herriot Hospital, 5 place d'Arsonval, F-69437 Lyon cedex 03, France. Back



   References
 Top
 Introduction
 Case 1
 Case 2
 Discussion
 References
 

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Received for publication: 11. 8.99
Revision received 6. 7.00.