Spontaneous remission of HCV-induced cryoglobulinaemic glomerulonephritis

Bertrand Dussol,1, Valérie Moal1, Laurent Daniel2, Christian Pain3 and Yvon Berland1

1 Service de Néphrologie et Hémodialyse, Hôpital Sainte Marguerite, Marseille, 2 Service d'Anatomie Pathologique, Hôpital Timone, Marseille, and 3 Centre d'Hémodialyse Sainte Marguerite, La Garde, France

Keywords: glomerulonephritis; hepatitis C virus infection; type II mixed cryoglobulinaemia



   Introduction
 Top
 Introduction
 Case
 Discussion
 References
 
The association between hepatitis C virus (HCV) infection and cryoglobulinaemic membranoproliferative glomerulonephritis (cryo-MPGN) has been described in many reports [13]. The clinical presentation and evolution of the renal disease may be variable [1].

This report describes the unusual course of cryo-MPGN in a patient suffering from chronic HCV infection. Since our patient spontaneously recovered his renal function after 6 months of dialysis, treatments of cryo-MPGN should take into account the highly unpredictable evolution of the glomerulonephritis.



   Case
 Top
 Introduction
 Case
 Discussion
 References
 
A 53-year-old man underwent renal evaluation in October 1996 for nephrotic syndrome and progressive renal failure.

His medical history was remarkable since chronic viral C hepatitis was diagnosed in 1991 and uncomplicated non-insulin-dependent diabetes mellitus (NIDDM) in 1993. Liver biopsy in 1991 revealed severe chronic hepatitis (Knodell score 13) and interferon-{alpha} (3 million units s.c. three times weekly) was prescribed. After 6 months, interferon-{alpha} was stopped because of failure to normalize transaminase levels and because of serious side-effects (autoimmune thyroitidis). In 1995 liver biopsy revealed cirrhosis.

In September 1996 the patient was admitted to the gastroenterology unit of Sainte Marguerite Hospital for abdominal pain. He also complained of asthenia and one episode of macroscopic haematuria. On admission serum creatinine was normal, but renal failure quickly occurred and the patient was transferred to the nephrology unit. On physical examination, his overall state was poor, supine blood pressure was 200/110 mmHg with lower-limb oedema, and diuresis of 1–1.5 l/day. No adenopathy or hepatosplenomegaly was present. Neurological, skin, and joint examinations were normal. No infections were present. Hypertension was treated with a loop diuretic and a calcium antagonist.

Laboratory investigations yielded the following results: serum creatinine 232 µmol/l, BUN 18 mmol/l, albumin 28 g/l, calcium 2.14 mmol/l and {gamma}-globulin 5%. Glycaemia and lipids were normal. Haemoglobin was 10 g/100 ml, white blood cells 11 300/mm3 with normal differential count, and platelets 234 000/mm3. C3 was 1 g/l (N, 0.5–1); C4 0.06 g/l (N, 0.2–0.6); IgM 3.2 g/l (N, 0.6–1.4); IgG 1.6 g/l (N, 7.5–11.7); and IgA 1.2 g/l (N, 0.6–2). Serum aminotransferases and bilirubin were normal, {gamma}-glutamyl-transferase ({gamma}GT) was 226 UI/l (N <30 UI/l), prothrombin time was normal. Proteinuria was 4.5 g/l with 85% albumin; urinary sediment revealed microscopic haematuria and leukocyturia. Immunofixation showed no free light chains in urine.

Hepatitis B serology was negative, and hepatitis C serology was positive (second-generation ELISA and RIBA). HCV RNA was detected by polymerase chain reaction (PCR). The genotype was 1b with very active replication (more than 4.105 copies/ml) measured by quantitative competitive PCR. Rheumatoid factor was positive and an abundant type II cryoglobulinaemia was present with a cryoprecipitate consisting of polyclonal IgG and monoclonal IgM-{kappa}. Tests for autoantibodies were negative. Renal and abdominal sonography showed two kidneys of normal size, normal liver, splenomegaly (13 cm), and low-volume ascites.

A kidney biopsy was performed. Eight glomeruli were observed by light microscopy. All displayed massive and diffuse hypercellularity due to mesangial cell proliferation and infiltration of polynuclear cells in the flocculus. Large subendothelial acidophilic deposits were observed. Numerous intraluminal thrombi were present in three glomerular tufts. A mild interstitial fibrosis was noted. Tubules and arterioles were strictly normal. Immunofluorescence revealed diffuse mesangial and subendothelial deposits of IgG, IgM, C3, C1q, and light chains (Figures 1Go and 2Go).



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Fig. 1. Glomerulus with thrombi stained with anti-IgG antibody. Few mild granulous parietal deposits were also present. (Immunofluorescence, original magnificationx250.).

 


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Fig. 2. Features of a cryoglobulinaemic glomerulonephritis with thick capillary walls and thrombi that obstruct capillary lumina. (Jones’ argentation, original magnificationx400.).

 
Soon after admission, the patient's condition worsened, with diffuse oedema refractory to loop diuretics, progressive oliguria, then anuria and aggravation of renal failure. The patient had to be dialysed 15 days after referral (Figure 3Go).



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Fig. 3. Evolution of the renal function between September 1996 and June 1999. Arrows indicate the treatment period.

 
Prednisone 1 mg/kg/day was begun associated with a bolus of cyclophosphamide 0.5 g/m2 that was repeated 3 weeks afterwards. No improvement of the nephrotic syndrome or the renal function was observed and the treatment was stopped after 6 weeks. A native arteriovenous fistula was created and the patient entered into a chronic haemodialysis programme. Total anuria permitted the nephrotic syndrome to be corrected. No other manifestations of HCV-induced cryoglobulinaemia were observed during the dialysis period.

Six months later (May 1997) diuresis progressively resumed, so haemodialysis became less frequent then stopped with frusemide (Figure 3Go). At that time the patient's overall condition was good, without oedema. Physical examination was unremarkable except for lower-limb purpura, raised papules, and leg ulcers that occurred by flares. Blood pressure was 135/80 mmHg without antihypertensive therapy. Skin biopsy confirmed cryoglobulin-induced vasculitis. In July 1997, laboratory investigations revealed: serum creatinine 150 mol/l, Cockcroft clearance 58 ml/min, albumin 45 g/l, no proteinuria, and normal urinary sediment. Serum aminotransferases and {gamma}GT were elevated, and TP was normal. HCV RNA was still present with an abundant type II cryoglobulinaemia and low total complement and fractions C3 and C4. Quantification of HCV RNA showed intense replication with more than 105 copies/ml. In October 1997, 4 months after the end of dialysis, a second kidney biopsy was performed. By light microscopy the 11 glomeruli displayed a diffuse but very mild endocapillary proliferation with focal subendothelial deposits. Interstitium, tubules, and arterioles were normal (Figure 4Go). By immunofluorescence, mesangial and subendothelial IgM deposits were observed in only two of the six glomeruli examined.



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Fig. 4. A non proliferant glomerulus with a moderate increase of the mesangial cellular matrix (Gomori trichrome, original magnificationx250.).

 
At the last examination (June 1999) serum creatinine was 123 µmol/l and proteinuria was 0.5 g/day. Blood pressure and urinary sediment were normal.



   Discussion
 Top
 Introduction
 Case
 Discussion
 References
 
In the present case, the diagnosis of HCV-induced cryo-MPGN is obvious. This patient was cirrhotic and had a nephrotic syndrome, both of which may have contributed to the renal damage. But the biopsy only evidenced typical lesions of cryoglobulin-induced MPGN.

On the other hand, the evolution of the glomerulonephritis was surprising. First, uraemia is rare in HCV-induced cryo-MPGN. It is observed in only 10% of the patients and usually more than 10 years after renal disease onset [1]. In our case the patient had reached end-stage renal failure necessitating haemodialysis in less than a month. Second, in HCV-induced cryo-MPGN, remission of renal symptoms such as acute nephritic syndrome or severe nephrotic syndrome is frequent. Remission occurs in nearly one-third of patients even before any treatment is started [1]. But such a dramatic improvement of our patient's nephrotic syndrome and 6 month renal failure has never been described to date. Thus it appears that in HCV-induced cryo-MPGN, improvement of the renal disease may occur even in case of apparently terminal renal failure and whatever the duration of the renal impairment.

The cause of renal improvement in our patient is not evident. Blood pressure control is an unlikely explanation since it was obtained as soon as dialysis was begun. Viral activity was the same before and during the dialysis period and thus cannot account for the renal recovery. The less unlikely hypothesis is a decrease in the patient's immune response induced by the dialysis sessions. Even though humoral response to HCV infection did not decrease since cryoglobulins were still present at the time of the recovery, it is possible that cell responses were less efficient due to the well-known haemodialysis cell defect.

This observation is important for two reasons. In this patient there was a complete dissociation between the activity of the cryoglobulinaemia and its renal and extrarenal manifestations. Such a dissociation has already been described [4]. In fact renal function improved when cryoglobulin was highly active since it induced skin vasculitis. Furthermore cryoglobulin was as abundant as at the time of the acute renal failure. Thus, in a patient with HCV-induced cryoglobulinaemia, renal and extrarenal manifestations may occur whatever the activity of the cryoglobulin. On the other hand the clinicopathological correlations were good, as evidenced by the dramatic improvement of the renal lesions in the second biopsy when the patient recovered his renal function.

The second reason is the therapy. In many isolated case reports, authors claimed that patients with HCV-induced cryo-MPGN improved their glomerulonephritis by using various drug regimens: interferon-{alpha} at the usual dosage (3 million units three times a week) or higher (6–10 million units three times a week, [5]), combination of interferon-{alpha}/ribavirin [6], steroids alone or with cyclosphosphamide [7], and cyclosphosphamide [8] or ribavirin alone [9]. In this case, a late response to steroids and cyclophosphamide is very unlikely, since it occurred 5 months after the treatment withdrawal. This rare observation of spontaneous improvement of renal disease raises the question of the true impact of the treatment in these case reports. In fact there are few studies on renal evolution in patients under treatment for HCV-induced cryo-MPGN [10,11]. Placebo-controlled studies should be conducted to assess the effectiveness of the treatments currently offered to patients suffering from HCV-induced cryo-MPGN [7,12].



   Notes
 
Correspondence and offprint requests to: Bertrand Dussol, Service de Néphrologie et Hémodialyse, Hôpital Sainte Marguerite, 270 Bd de Sainte Marguerite, BP 29, F-13274 Marseille Cedex 09, France. Back



   References
 Top
 Introduction
 Case
 Discussion
 References
 

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Received for publication: 22.11.99
Revision received 17. 8.00.



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