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ORIGINAL ARTICLE Table of Contents   
Year : 2010  |  Volume : 53  |  Issue : 4  |  Page : 672-675
Polyomavirus nephropathy and Cytomegalovirus nephritis in renal allograft recipients


1 Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow- 226014, India
2 Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow- 226014, India

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Date of Web Publication27-Oct-2010
 

   Abstract 

Background: Polyomavirus nephropathy (PVN) and Cytomegalovirus (CMV) disease are the most common viral pathogens causing allograft dysfunction in renal allograft recipients. They have been observed in transplant recipients with increasing frequency in the recent years with various reports describing wide differences in the incidence of these infections in renal allografts. We present our experience with Polyomavirus (PV) infection and CMV infection in allograft of renal transplant recipients from a transplant centre in North India performing more than 100 transplants per year. Materials and Methods: 390 renal allograft specimens from 327 patients over a 4 year period, presenting with renal dysfunction were re-evaluated for presence of PVN and CMV disease utilizing histo-morphological features and immunohistochemistry. Results: Thirteen patients with PVN and four with CMV disease were identified. All patients were on triple drug immunosuppression receiving cyclosporine, prednisolone and tacrolimus or MMF. The mean period of diagnosis of viral infection after transplant was 12.4 months (seven days to 3.5 yrs) for PVN and 4.8 months (two to seven months) for CMV nephritis. Biopsies showed varying degrees of tubulointerstitial inflammation, viral inclusions and evidence of tubular damage. Associated features of acute rejection were present in 69.2% of patients with PVN. Conclusion: Histological features of PVN involving the kidneys have considerable morphological overlap with acute rejection while CMV disease presents primarily as tubulointerstitial inflammation. We observed a prevalence of 4% for PVN and 1.2% for CMV nephritis in renal allografts.

Keywords: Cytomegalovirus infection, polyomavirus nephropathy, renal allograft, viral infection

How to cite this article:
Agrawal V, Gupta RK, Jain M, Prasad N, Sharma RK. Polyomavirus nephropathy and Cytomegalovirus nephritis in renal allograft recipients. Indian J Pathol Microbiol 2010;53:672-5

How to cite this URL:
Agrawal V, Gupta RK, Jain M, Prasad N, Sharma RK. Polyomavirus nephropathy and Cytomegalovirus nephritis in renal allograft recipients. Indian J Pathol Microbiol [serial online] 2010 [cited 2014 Aug 29];53:672-5. Available from: http://www.ijpmonline.org/text.asp?2010/53/4/672/72025



   Introduction Top


Viral infections are an important cause of allograft dysfunction in renal transplant recipients. They have been observed in transplant recipients with increasing frequency in the recent years. This is largely due to the use of more potent immunosuppressive therapy.

PVN is presently described as the most important infection involving kidney transplants. [1] PVN and CMV are the most common viral etiological agents in renal allograft recipients. PVN has been attributed to reactivation of BK virus (BKV) or more rarely JC virus. Detection of viral infection associated graft dysfunction requires a judicious decrease in immunosuppression and monitoring for acute rejection. Histological features of viral infection involving the kidneys are not very distinct and have a morphological overlap with features of acute rejection. Asymptomatic primary PV (BK Polyoma) infection is seen in most individuals during early life. It remains latent in the urinary tract and gets reactivated with immunosuppresssion in renal transplant recipients. The incidence of PVN has been variably reported to be up to 10% in literature. [2],[3],[4] A high incidence of BKV nephropathy has been earlier reported from India. [4]

CMV nephritis can arise from reactivation of recipient's latent strain or from primary infection or super-infection with virus from the donor kidney. CMV infection in the allograft kidney has a wide spectrum of histological appearances varying from scattered inclusion bodies without inflammatory response to severe interstitial nephritis. There are occasional reports of CMV infection in renal allograft recipients in the literature. [5],[10],[11],[12] Occurrence of CMV inclusions in renal tissues examined is infrequent, seen in less than 1% of renal allograft biopsies. [5]

We present a single centre experience with PV infection and CMV infection in allograft of renal transplant recipients. Histological evaluation for viral cytopathic effects and immunohistochemistry for polyoma and CMV were used to estimate the occurrence of these infections.


   Materials and Methods Top


We evaluated all renal allograft specimens received in the period from January 2003 to December 2006. Ours is a tertiary care hospital and transplant center with more than 100 renal transplant performed per year. The study included 390 specimens (385 needle biopsies, five graft nephrectomies) from 327 patients of live renal transplants presenting with graft dysfunction. Clinical and biochemical data were recorded. Light microscopic re-evaluation of formalin fixed paraffin - embedded tissue sectioned at 2-4 μm and stained with hematoxylin and eosin, periodic acid Schiff, periodic silver methenamine and Mason trichrome was performed. Biopsies were evaluated according to the Banff 97' diagnostic categories [Table 1]. [6] Careful histological examination was done for morphological evidence of viral infections [Table 2]. [1] Immunohistochemistry was performed in the suspected cases and an equal number of allograft biopsies with no suspicion of viral infection for both CMV and PV using Monoclonal Anti- CMV antibody (Clone CCH 2; Dako, Denmark 1:50 dilution) and Monoclonal Anti- SV40 Large T cell Antigen Antibody (Clone PAb100; BD Biosciences 1:25 dilution) respectively with labeled Streptavidin Biotin technique (LSAB 2+ kit Dako, Denmark) using diaminobenzidine (DAB) as chromogen.


   Results Top


Of the 327 patients, 292 were males and 35 females and the mean age was 37.2 years (range 14-67 years). All the patients were on triple drug immunosuppression (cyclosporine, prednisolone and mycophenolate mofetil or tacrolimus). After careful histological examination suspicion of viral infections was raised in 46 biopsies [Table 1]. Immunohistochemistry was performed in these cases and an equal number of allograft biopsies with no suspicion of viral infection. Immunohistochemistry revealed nuclear viral staining for Polyoma in 13 and CMV in four of the suspected cases, while it was negative in all the controls. All the biopsies showed predominantly mononuclear interstitial inflammation composed of lymphocytes and plasma cells. PVN showed focal viral cytopathic changes in the tubular epithelial cells associated with marked tubular damage and a disproportionate mild degree of tubulitis [Figure 1]. The changes were seen in both distal and proximal tubules and the involved tubules were found interspersed among normal appearing tubules. The affected tubular epithelial cells showed a maintained or a mildly increased cell size, mild to moderate nucleomegaly and nuclear inclusions. The nuclear inclusions were predominantly type I and type III [Table 2]. Associated changes of acute rejection were observed in nine of the 13 biopsies with PVN. No lesions were seen in the glomeruli or blood vessels.
Table 1 :Diagnostic categories and cases morphologically suspicious of viral infections in Renal Allografts


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Table 2 :Morphological features for suspicion of viral Infections


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Figure 1 :Viral inclusions in tubular epithelial cells in a renal biopsy of PVN (H and E, ×400)

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CMV infection predominantly showed varying degrees of tubulointerstitial nephritis with presence of viral cytopathic changes. Areas of cortical necrosis were present in one patient, who also had extrarenal histologically proven CMV disease in form of cutaneous ulcers with vasculopathy [Figure 2]. The comparative histological and clinical features of both viral infections are given in [Table 3].
Table 3 :Comparative features of PVN and CMV disease


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Figure 2 :CMV disease (a) Renal biopsy in a patient showing areas of cortical necrosis and viral inclusions in tubular epithelial cells, (b) similar features in vascular endothelial cells in skin biopsy (H and E, x400). (c) Immunohistochemistry for CMV using DAB as chromogen showing heterogeneous nuclear positivity (Monoclonal Mouse Anti- CMV antibody)

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PCR for BK PV was done on blood sample in only one of the cases and revealed more than 10,000 copies. PCR for CMV DNA on blood sample was done in two of the four cases and showed more than 500 copies in both. All the three patients with diagnostic viral copies detected on PCR improved after appropriate therapy and timely reduction in immunosuppression.


   Discussion Top


Infection in a renal transplant recipient is an important cause of morbidity and mortality. They are often detected late or remain undetected due to the impaired inflammatory responses caused by immunosuppressive therapy in these patients. Many of these infections mimic non-infectious processes namely graft rejection and drug toxicity, making timely diagnosis more difficult.

Viral pathogens are responsible for graft dysfunction one to six months post transplant (period of intense immunosuppression) and also beyond 6- 12 months (due to community acquired exposures according to the level of maintenance immunosuppression). [7] PVN can present with graft dysfunction 6 days to 6 years post transplant (mean 380 days). [2],[4],[8],[9] The mean period of diagnosis of viral infection after transplant in our study was 12.4 months (7 days to 3.5 years) for PVN and 4.8 months (2-7 months) for CMV nephritis.

Certain immunosuppressive agents like calcineurin inhibitors and mycophenolate mofetil are associated with an increased risk for viral infections. [7] Our patients were receiving a triple drug regimen of cyclosporine, prednisolone and mycophenolate mofetil or tacrolimus.

PVN has been variably reported in literature and has a prevalence of 1- 10%. [2],[3] An earlier Indian study has reported it to be 9.3%. [4] We report a prevalence of 4% for PVN. Infection of the allograft presents most commonly as rising serum creatinine (92.3%, 12/13). Associated histological features of acute rejection were present in nine of the thirteen patients (69.2%). Viral infections are considered potential risk factors for acute allograft rejection in renal transplant recipients.

CMV nephropathy presenting as viral inclusions has been sporadically reported. [5] Reports suggest that quantitative and qualitative blood PCR for CMV is a more sensitive technique to detect CMV disease. [10] CMV disease has been implicated as a risk factor for acute transplant rejection. In our study we report a prevalence of 1.2% for CMV nephritis, presenting as graft dysfunction. None of the patients had morphological evidence of acute rejection and showed varying degrees of tubulointerstitial inflammation with presence of nuclear viral inclusions in tubular and endothelial cells. Cortical necrosis, uncommonly reported in literature was seen in one of our patients. [11] A previous study from India has reported a prevalence of 1.9% for CMV nephritis. [12]

Summarizing, PV-associated nephropathy more commonly presents as acute rejection than CMV nephritis, which commonly shows varying degrees of acute tubulointerstitial nephritis. We report a prevalence of 4% for Polyoma and 1.2% for CMV nephritis at our transplant center.

 
   References Top

1.Colvin RB, Nickeleit V. Renal Transplant Pathology. In: Jennette CJ, Olson JL, et al. editors. Heptinstall's Pathology of the Kidney. 6th ed. Lippincott Williams and Wilkins; 2006. p. 1441.   Back to cited text no. 1
    
2.Nickeleit V, Mihatsch MJ. Polyomavirus nephropathy in native kidneys and renal allografts: an update on an escalating threat. Transpl Int 2006;19:960-73.  Back to cited text no. 2
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3.Drachenberg CB, Hirsch HH, Ramos E, Papadimitriou JC. Polyomavirus disease in renal transplantation: Review of pathological findings and diagnostic methods. Hum Pathol 2005;36:1245-55.   Back to cited text no. 3
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4.Sachdeva MS, Nada R, Jha V, Sakhuja V, Joshi K. The high incidence of BK polyomavirus infection among renal transplant recipients in India. Transplantation 2004;77:429-31.  Back to cited text no. 4
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5.Kashyap R, Shapiro R, Jordan M, Randhawa PS. The clinical significance of Cytomegalo viral inclusions in the allograft kidney. Transplantation 1999;67:98-103.  Back to cited text no. 5
[PUBMED]  [FULLTEXT]  
6.Racusen LC, Colvin RB, Solez K, Mihatsch MJ, Halloran PF, et al. Antibody-mediated rejection criteria - an addition to the Banff 97 classification of renal allograft rejection. Am J Transplant 2003;3:708-14.  Back to cited text no. 6
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7.Fishman JA. Infection in renal transplant recipients. Semin Nephrol 2007;27:445-61.  Back to cited text no. 7
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8.Vasudev B, Hariharan S, Hussain SA, Zhu YR, Bresnahan BA, Cohen EP. BK virus nephritis: risk factors, timing, and outcome in renal transplant recipients. Kidney Int 2005;68:1834-9.  Back to cited text no. 8
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9.Kim HC, Hwang EA, Kang MJ, Han SY, Park SB, Park KK. BK virus infection in kidney transplant recipients. Transplant Proc 2004;36:2113-5.  Back to cited text no. 9
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10.Liapis H, Storch GA, Hill DA, Rueda J, Brennan DC. CMV infection of the renal allograft is much more common than the pathology indicates: a retrospective analysis of qualitative and quantitative buffy coat CMV-PCR, renal biopsy pathology and tissue CMV-PCR. Nephrol Dial Transplant 2003;18:397-402.  Back to cited text no. 10
[PUBMED]  [FULLTEXT]  
11.Joshi K, Nada R, Radotra BD, Jha V, Sakhuja V. Pathological spectrum of cytomegalovirus infection of renal allograft recipients-an autopsy study from north India. Indian J Pathol Microbiol 2004;47:327-32.  Back to cited text no. 11
    
12.Sachdeva MU, Nada R, Jha V, Joshi K. Viral infections of renal allografts--an immunohistochemical and ultrastructural study. Indian J Pathol Microbiol. 2004; 47(2):189-94.  Back to cited text no. 12
    

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Correspondence Address:
Vinita Agrawal
Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow- 226014, Uttar Pradesh
India
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DOI: 10.4103/0377-4929.72025

PMID: 21045390

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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]

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