Primary Epstein–Barr virus infection and recurrent type I membranoproliferative glomerulonephritis after renal transplantation

Margret B. Andresdottir1,, Karel J. M. Assmann2, Luuk B. Hilbrands1 and Jack F. M. Wetzels1

1 Department of Internal Medicine, Division of Nephrology, and 2 Department of Pathology, University Hospital Nijmegen, The Netherlands

Keywords: Epstein–Barr virus; membranoproliferative glomerulonephritis; transplantation



   Introduction
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 Introduction
 Case
 Discussion
 References
 
Most patients with type I membranoproliferative glomerulonephritis (MPGN) progress toward end-stage renal disease, and after cadaveric transplantation the disease will recur in up to 50% of the patients [1]. In recent years an association between hepatitis C virus infection and the development of type I MPGN has been suggested [2,3]. We report a patient with type I MPGN who developed a recurrence of his disease within 7 months after transplantation. The development of the glomerulonephritis coincided with the onset of a primary Epstein–Barr virus (EBV) infection. A graft biopsy demonstrated the presence of EBV in the podocytes, suggesting that the EBV infection may have triggered the glomerular disease.



   Case
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 Introduction
 Case
 Discussion
 References
 
Our patient, a Caucasian boy, developed proteinuria and haematuria in 1993 at the age of 16 years. A renal biopsy was performed in 1994, and disclosed a type I MPGN. At the time of the biopsy serum creatinine was normal (75 µmol/l), complement levels were slightly decreased (C3, 619 mg/l, and C4, 105 mg/l), and cryoglobulins were not detected. Proteinuria was in the nephrotic range (9 g/day). Over the next 2 years renal function rapidly deteriorated.

In 1996 the patient received a renal transplant from his healthy father. IgG antibodies against the viral capsid antigen of EBV (IgG-VCA), the early antigen (EA) and the nuclear antigen of EBV (EB-NA) were absent in both donor and recipient. The recipient also tested negative for cytomegalovirus, hepatitis B, and hepatitis C. The basic immunosuppressive therapy consisted of cyclosporin (CsA) (10 mg/kg, tapered to 4 mg/kg at 3 months) and prednisone (100 mg/day for the first 3 days, tapered to 0.15 mg/kg at 4 months). There was an immediate graft function and the early postoperative period was uneventful. The serum creatinine level at discharge, 8 days after transplantation, was 132 µmol/l and there was no proteinuria. The complement levels were normal. Five weeks after transplantation, the CsA dose was lowered and azathioprine was added to the immunosuppressive treatment because of a suspected CsA nephrotoxicity.

Seven months after transplantation the patient experienced malaise and fever, and symptoms of an upper respiratory tract infection. On physical examination no abnormalities were noted, in particular lymph nodes were not enlarged and there was no splenomegaly. Routine laboratory investigations were normal, specifically no proteinuria was detected. Over the following weeks the patient had few complaints but tiredness.

On laboratory examination IgG and IgM antibodies against EBV-VCA and EA were positive, indicating a primary EBV infection. At this time a proteinuria of up to 5.9 g/day was noted. The serum creatinine level was stable around 150 µmol/l. A transplant biopsy was not done because of an unexplained prolonged bleeding time. In order to minimize the risk of developing a post-transplant lymphoma, the immunosuppressive load was reduced by withdrawal of CsA. In addition, because of the proteinuria, treatment with an ACE inhibitor was started. When the patient's renal function deteriorated at 10 months post-transplantation, a renal biopsy was done despite the prolonged bleeding time. At the time of biopsy, the serum creatinine level was 195 µmol/l and the protein excretion was 8.8 g/10 mmol creatinine. No paraproteins were found in serum or urine. The complement levels were normal and cryoglobulins were negative. The biopsy specimen revealed an interstitial infiltrate consisting predominantly of T lymphocytes. This suggested an acute interstitial rejection rather than EBV-related inflammation.

The glomeruli demonstrated a membranoproliferative pattern of injury (Figure 1Go). By immunofluorescence, granular deposits of IgG, C1q, C3 and kappa light chains were found in the glomerular capillary wall and the mesangium (Figure 1Go). In about 25% of the glomeruli mild crescent formation was seen. By electron microscopy, electron-dense deposits were localized in the subendothelial space, and sporadically in the subepithelial space. In the glomeruli no structures compatible with EBV could be found. Immunohistochemical examination for EBV antigen was performed on Bouin's fixed kidney biopsy by an indirect immunoperoxidase technique, using mouse anti-human antibody specific for EBV viral capsid antigen (Dako, Denmark). EBV could be demonstrated in the cytoplasm of the glomerular podocytes, but not in the deposits and not in the infiltrating cells in the interstitium or in tubular epithelial cells. Because of the acute interstitial rejection, 1 g methylprednisolone was given intravenously on three consecutive days. This treatment had no effect on proteinuria or kidney function.



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Fig. 1. a Light microscopy of the renal transplant specimen with a picture of a membranoproliferative glomerulonephritis. There is an increase of mesangial cells and matrix, and reduplication of the glomerular basement membrane (arrows) with cellular interposition (Methenamine silver staining,x340). b. Immunofluorescence picture with granular C3 deposits mainly in the capillary walls of the glomerulus (x 400).

 
The clinical course thereafter was characterized by continued malaise, repeated upper respiratory tract infections, fluid retention, and hypertension. The kidney function deteriorated further while the nephrotic syndrome persisted. In July 1997, CAPD was started and transplantectomy was performed. The histology showed comparable morphological and immunohistological lesions as described for the previous transplant biopsy (Figure 1Go). Specifically, EBV antigen was still present in the glomerular visceral epithelial cells (Figure 2Go).



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Fig. 2. Immunohistological localization of EBV in podocytes (arrows) of the glomerulus detected with mouse anti-human EBV (Dako) (x 850). G, glomerulus.

 



   Discussion
 Top
 Introduction
 Case
 Discussion
 References
 
This patient developed a recurrent type I MPGN after transplantation associated with a primary EBV infection. Several data point to a causal relationship between the EBV infection and the development of the glomerulonephritis. First, the clinical findings in this patient are different from our experience in a series of 12 patients with a recurrent type I MGPN [1]. In these latter patients the onset of the recurrence was at a median of 20 months, starting with moderate proteinuria and progressing only slowly to nephrotic range proteinuria. In our patient the recurrence developed earlier, with a rapidly progressive proteinuria. Second, the onset of the recurrence coincided with the development of a primary EBV infection, and finally, the virus was found in the cytoplasm of the podocytes.

In the last 10 years a growing number of reports have been published on the relationship between chronic hepatitis C infection and membranoproliferative glomerulonephritis, both in the native and the transplanted kidney [2,3]. These observations have led to increased awareness of the potential role of other viruses in inducing type I MPGN. It remains difficult, however, to prove a causal relationship between the viral infection and the development of type I MPGN. In most cases of hepatitis C induced type I MPGN viral antigens cannot be found in the glomerulus. However, this certainly does not exclude that viruses are involved; some immune complexes do not necessarily contain viral antigens, but are rather composed of endogenous antigens released by viral-induced injury to cells [4].

Alternatively, the finding of a viral antigen in glomerular epithelial cells as in our patient does not prove that the virus is responsible for the glomerular disease. It has been suggested that in some forms of glomerular disease the presence of viral antigens in the glomerulus may represent non-specific trapping of the antigens in the glomerular capillaries [5]. Furthermore, in our patient the localization of the virus was different from the localization of the immune deposits, again suggesting that the antigens in the immune deposits may not correspond with viral antigens. We are aware of two other case reports where viruses have been encountered in the glomerulus of patients with a recurrent type I MPGN in the renal graft. Sonnabend et al. [6] described a patient with type I MGPN after renal transplantation in whom hepatitis B as well as EBV infection developed and the viral particles were found mainly in the subendothelial immune deposits. Birk and Chavers [7] recently reported a patient with a recurrent type I MPGN in whom CMV inclusions were present in the glomerular epithelial cells at the time of a primary CMV infection.

EBV-induced infectious mononucleosis has been implicated in the development of renal disease. Most frequently EBV virus infection has been associated with an interstitial nephritis, sometimes leading to acute renal failure [8,9]. Few reports have described the occurrence of glomerular abnormalities. Ramelli et al. [9] have reviewed the results of renal biopsies in 36 patients with infectious mononucleosis. In 14 patients glomerular abnormalities were found, the glomerular pathology being quite diverse, ranging from minimal-change to focal sclerosis, and proliferative or sclerosing glomerulonephritis. In their review Mayer et al. [8] mention two patients with an immune complex glomerulonephritis characterized by deposits in the subepithelial space and the mesangium respectively. Another pattern of injury was recently described by Lande et al. [10]. Their patient presented with a sore throat, fever, and a rash. Shortly after she developed purpura and an acute renal failure. A biopsy of the skin disclosed a leukocytoclastic vasculitis. In the kidney glomeruli showed a typical picture of an acute endocapillary exudative glomerulonephritis. By electron microscopy, multiple small deposits were observed in the subendothelial space and in the mesangium, and a single large deposit was noted subepithelially, all features of an acute post-infectious glomerulonephritis. Finally, Dror et al. [11] have suggested a link between EBV and SLE. In their patient, the onset of SLE concurred with an acute EBV infection and the EBV antigen was also detected in the visceral epithelial cells.

In conclusion, a primary EBV infection may trigger the recurrence of a type I MPGN after renal transplantation. It remains to be seen if an EBV infection can induce a similar pattern of glomerular injury also in patients with an other original renal disease.



   Acknowledgments
 
M. B. Andresdottir is supported by a grant from the Dutch Kidney Foundation (C96.1543). We thank Mr H. Dijkman for his skilful help in performing the histology and electron microscopy and in preparing the morphological pictures.



   Notes
 
Correspondence and offprint requests to: M.B. Andresdottir MD, Dept of Internal Medicine, Div of Nephrology, University Hospital Nijmegen, PO BOX 9101, NL-6500 HB Nijmegen, The Netherlands. Back



   References
 Top
 Introduction
 Case
 Discussion
 References
 

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Received for publication: 3.11.99
Revision received 13. 3.00.



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