Nephrol Dial Transplant (2001) 16: 869-871
© 2001 European Renal Association-European Dialysis and Transplant Association
Letters
Hepatitis C-associated glomerulonephritis—a novel therapeutic approach
1 Department of Medicine 2 Department of Pathology 3 Wellcome Trust Centre for Molecular Mechanisms in Disease Cambridge Institute for Medical Research, University of Cambridge, School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK
Sir,
We report the case of a man with cryoglobulinaemic mesangiocapillary glomerulonephritis (MCGN) associated with chronic hepatitis C virus (HCV) infection who was treated successfully with mycophenolate mofetil (MMF) and interferon-
.
Case.
A 51-year-old male presented with a 5-week history of malaise, dyspnoea and diarrhoea, abdominal pain and distension, and a 3-day history of face and ankle oedema. He had a past history of intravenous drug abuse but no other risk factors for HCV infection. On admission his blood pressure was 180/115, pulse 95 min, temperature 37.2°C and he had mild dependent oedema. Laboratory evaluation showed Hb 9.9 g/dl, leucocytes 13.8x109/l, urea 12.7 mmol/l, creatinine 150 µmol/l, albumin 21 g/l and normal liver function. Urinalysis showed proteinuria ++ and blood ++ and a 24-h urine collection demonstrated 6.4 g of protein and a creatinine clearance of 61.8 ml/min. Hepatitis HCV antibody was detected in serum by ELISA and HCV-RNA in serum by PCR. The patient was hepatitis B surface antigen negative. Other laboratory results showed IgG 4.7 g/l (6–13), IgA 1.1 g/l (0.80–3.70), IgM >5.5 g/l (0.40–2.20), rheumatoid factor 1320 IU/ml (0–30), C3 1.09 g/l (0.80–2.14) C4 0.10 g/l (0.13–0.60) and cryocrit 30%. Immunofixation revealed these serum cryoglobulins to be type II according to the Bruer classification (monoclonal IgM
and polyclonal IgG). An ultrasound of his abdomen and kidneys was normal and anti-hypertensive treatment was started.
Renal biopsy showed 16 glomeruli, all of which were diffusely and uniformly abnormal with features characteristic of a cryoglobulinaemic MCGN type 1. Liver biopsy showed stage 3 fibrosis. Immunosuppression was not commenced to avoid exacerbation of his liver disease, given his renal function was stable. His oedema was controlled and he was discharged.
One week later he was re-admitted with worsening oedema and a decline in renal function. It was decided to suppress his HCV liver disease with interferon- before commencing treatment for his cryoglobulinaemic MCGN. Interferon- was commenced at 5 million units for 5 days followed by 3 million units three times a week. Ten days later he commenced 5 days of plasma exchange, and MMF at a dose of 1 g b.i.d. On this treatment serum creatinine fell, cryocrit fell to 5% and then to undetectable levels, and all systemic symptoms resolved (Figure 1
).
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He still remains symptom-free 18 months after discharge, with serum cryoglobulins remaining low and serum HCV-RNA undetectable. Creatinine returned to, and remains at, the upper limit of normal and liver function is normal.
Comment.
Conventional treatment for cryoglobulinaemic MCGN is problematic and has involved the use of corticosteroids, cyclophosphamide, interferon- and plasma exchange. Corticosteroids are useful in acute flare ups, although there is evidence that their use accelerates HCV related hepatic fibrosis undetected by conventional liver function tests [1]. Interferon- has been shown to have a modest short-term effect on alanine transaminase levels and serum HCV-RNA in patients with chronic HCV infection. It has also been shown to reduce cryoglobulin levels temporarily and reduce clinical manifestations of the disease in patients with associated mixed cryoglobulins [2]. No studies have investigated its effect on cryoglobulin-associated renal disease. The efficacy of interferon- may be related to viral load, viral genotype and liver histology, but less than 50% of patients respond initially to treatment, and relapse is common after cessation of treatment. Plasma exchange removes circulating cryoglobulins, thereby inducing a temporary remission; however, it has no effect on underlying cryoglobulin production and, therefore, has no long term benefit. Cyclophosphamide treatment is aimed at inhibiting B lymphocyte production of the monoclonal rheumatoid factors that form part of the cryoglobulins. There is evidence that cyclophosphamide can cause worsening of HCV viraemia and accelerate HCV-related liver disease. There is little published experience of MMF use in renal disease nor its use in the treatment of MCGN.
MMF has been shown to have two important properties which appear to be ideally suited to the treatment of hepatitis C-associated cryoglobulinaemic MCGN. First, it has been shown to have a more potent anti-B cell action that other conventionally used immunosuppressants [3], suppressing the humoral immune response to influenza vaccination profoundly when used in combination with prednisolone and cyclosporin, compared with azathioprine used with this combination [4]. Second, there appears to be evidence that MMF has an anti-HCV effect. It has been shown to reduce both viral load and aspartate transaminase in patients with HCV infection undergoing liver transplantation [5].
A reduction in hepatitis C viral-load was demonstrated in our patient between the time of his admission and after the resolution of his symptoms. Interferon- has only been shown to benefit patients with hepatitis C cryoglobulinaemia if it is associated with complete eradication of HCV-RNA from the serum. The relative contributions of interferon- and the proposed anti-viral effect of MMF to the observed reduction in HCV-RNA in this patient are unclear, but substantial loss of HCV-RNA occurs in only 8% of all patients with HCV treated with interferon- alone.
In conclusion, the successful use in this patient of MMF and interferon- offers a safer and more effective approach to treating a disease where current therapy is unsatisfactory. An initial reduction in cryocrit level was achieved with plasma exchange, but maintained with MMF, perhaps through MMF's potent ability to suppress humoral immunity. Concurrently HCV was controlled by interferon-, with an additional anti-viral contribution possibly being made by MMF. More potent and potentially harmful immunosuppression was therefore avoided.
References
- McHutchinson JG, Wilkes LB, Pockros PJ. Pulse corticosteroid therapy increases viremia (HCA-RNA) in patients with chronic HCV infection (abstract). Hepatology1993; 18: 87A
- Mazzaro C, Carniello GS, Colle R et al. Interferon therapy in HCV-positive mixed cryoglobulinaemia: viral and host factors contributing to efficacy of the therapy. Italian J Gastroenterol Hepatol1997; 29: 343–350[Web of Science][Medline]
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Van der Woude FJ. Mycophenolate mofetil (RS61443). Nothing new under the sun or an important break-through in the field of transplantation? Nephrol Dial Transplant1995; 10: 1112–1115
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Smith KGC, Isbel NM, Catton MG et al. Suppression of the humoral immune response by mycophenolate mofetil. Nephrol Dial Transplant1998; 13: 160–164
[Abstract/Free Full Text] - Platz KP, Muellar AR, Willimski C et al. Indications for mycophenolate therapy in hepatitis C patients undergoing liver transplantation. Transplant Proceed1998; 30: 2232–2233
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