Is it rejection? Be on the lookout for decoys
Shaun A. Summers1,
Chris Laing1,
Terence H. Cook2 and
Patrick H. Maxwell1
1 Department of Renal Medicine and 2 Department of Histopathology, Hammersmith Hospitals, London, UK
Correspondence and offprint requests to: Shaun A. Summers, Department of Renal Medicine, Hammersmith Hospitals, London, UK. Email: shaunsummers{at}hotmail.com
Keywords: BK polyomavirus; cellular rejection; decoy cells; nephropathy; tubulitis
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Introduction
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We describe the case of a renal transplant recipient, who suffered from acute renal dysfunction, in whom renal biopsy showed findings consistent with acute cellular rejection. He was treated with pulsed steroid therapy. After further investigations, a diagnosis other than rejection was made, which highlights an increasingly important clinical problem in the course of renal transplantation.
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Case
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A 47-year-old man of Pakistani origin underwent live-unrelated renal transplantation (1, 2, 1 mismatch) after reaching end-stage renal failure. His immunosuppression regime consisted of tacrolimus, mycophenolate mofetil (MMF) and prednisolone.
Following an uneventful recovery from surgery, his creatinine improved, ranging between 100 and 120 µmol/l. There were no acute rejection episodes.
Five months after the operation, he was admitted for investigation of a rise in creatinine to 170 µmol/l. Ultrasound showed a transplanted kidney of normal size, shape and echotexture. There was no clinical or laboratory evidence of urinary or systemic sepsis. Renal biopsy was performed and showed widespread mononuclear cell infiltration and tubulitis compatible with acute cellular rejection (Figure 1). He was treated with intravenous methylprednisolone (500 mg) for four consecutive days.

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Fig. 1. The kidney shows a prominent interstitial infiltrate of mononuclear inflammatory cells with tubular epithelial cell damage and infiltration of inflammatory cells into tubules (tubulitis). Haematoxylin and eosin staining.
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Additional immunohistochemistry demonstrated the presence of polyoma viral antigen (Figure 2). Decoy cells were found in the urine and BK viral DNA in the plasma, detected by polymerase chain reaction (PCR). In the light of this, his prednisolone was tapered and stopped and his MMF was also stopped. His creatinine stabilized in the range 180220 µmol/l.

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Fig. 2. Immunohistochemistry shows that many tubular nuclei stain with an antibody to SV40 large T antigen, indicating polyoma virus infection. Immunoperoxidase with haematoxylin counterstain.
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Discussion
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BK polyomavirus is a double-stranded DNA virus belonging to the papovavirus family and infects up to 90% of the general population.
The most important clinical manifestations related to BK polyomavirus are haemorrhagic cystitis following bone marrow transplantation, and ureteral stenosis and interstitial nephropathy in kidney transplant recipients [1]. The incidence of BKV nephropathy has risen from 1% of patients transplanted in 1997 to
5% [2,3]. The presentation can be subtle, with a rise in serum creatinine often the only detectable anomaly. There is considerable variation in the time from transplantation to the diagnosis of BKV nephropathy. Ramos et al. [2] found a mean time of 14.4 months in their transplant population, whilst Kim et al. [3] reported a median time to diagnosis of BKV infection of 7.8 months following transplantation. BKV nephropathy is a significant cause of graft loss. Ramos et al. [2] found that as many as a third of patients lost their grafts whilst a further third had a rise in creatinine.
Our patient presented at 5 months with a rising creatinine. Given the 1, 2, 1 mismatch, there was concern that this represented acute cellular rejection, and a renal biopsy was performed. The biopsy preceded the study of urine or serum for suggestions of polyoma viraemia.
Non-invasive screening for BKV nephropathy can be achieved through microscopic analysis of cells in the urine for the presence of viral inclusions, which are known as decoy cells. Although the presence of decoy cells is a very sensitive indicator of BKV replication in the urinary tract, the positive predictive value for BKV nephropathy may be <20%. Plasma can be tested for BKV DNA, using PCR, which suggests significant BKV nephropathy (quoted sensitivity 100%, specificity 88%) [4]. These tests provide a useful means of screening allograft recipients for BKV nephropathy. Although not easily seen in this case, with careful examination of the haematoxylin and eosin sample, one may find the typical nuclear inclusions in tubular epithelium on biopsy. The diagnosis is established by the presence of viral antigen in the nuclei of tubular epithelial cells using immunohistochemistry or in situ hybridization.
The optimal management of BKV nephropathy remains controversial. There is no proven benefit from antiviral therapy, and reduction of immunosuppression remains the favoured approach. BKV nephropathy can co-exist with acute rejection, and some authors favour a short-term increase in immunosuppressive therapy [5,6] to treat the acute rejection. However, Celik et al. reported a significant improvement in renal biopsy findings when reducing immunosupression compared with administering pulsed steroid therapy. In their study, reducing immunosuppression in those patients with polyoma virus allograft nephropathy and tubulitis was more effective in lowering viral load than steroid therapy [7]. Regardless of the immediate strategy, reducing immunosuppression is the standard approach to the longer term management of BKV nephropathy. This requires a secure diagnosis, together with close monitoring of graft function.
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Teaching points
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- BKV nephropathy needs to be considered in all renal allograft recipients with a rising creatinine, regardless of the time since transplantation.
- There is a strong case for routine screening of renal transplant patients with urine cytology, looking for decoy cells. The presence of decoy cells in the urine should alert to the possibility of BKV nephropathy and is an indication for quantitative measurement of viral load in plasma.
- A diagnosis of BKV nephropathy requires the demonstration of viral antigen in the renal tubular cells, which is technically straightforward to do. The features of the biopsy are variable, and may be consistent with acute cellular rejection. The diagnosis has important implications for treatment, and the overall aim should be to reduce the dose of immunosuppression.
Conflict of interest statement. None declared.
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References
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- Hirsch HH, Knowles W, Dickenmann M et al. Prospective study of polyomavirs type BK replication and nephropathy in renal transplant recipients. N Engl J Med 2002; 347: 488496[Abstract/Free Full Text]
- Ramos E, Drachenberg CB, Portocarrero M et al. BK virus nephropathy diagnosis and treatment: experience at the University of Maryland Renal Transplant Program. Clin Transplant 2002; 143153
- Kim HC, Hwang EA, Kang MJ et al. BK virus infection in kidney transplant recipients. Transplant Proc 2004; 36: 21132115[CrossRef][ISI][Medline]
- Baksh FK, Finkelstein SD, Swalsky PA et al. Molecular genotyping of BK and JC viruses in human polyomavirus-associated interstitial nephritis after renal transplantation. Am J Kidney Dis 2001; 38: 354365[ISI][Medline]
- Nickeleit V, Singh HK, Mihatsch MJ. Polyomavirus nephropathy: morphology, pathophysiology, and clinical management. Curr Opin Nephrol Hypertens 2003; 12: 599605[ISI][Medline]
- Nickeleit V, Mihatsch MJ. Polyomavirus allograft nephropathy and concurrent acute rejection: a diagnostic and therapeutic challenge. Am J Transplant 2004; 4: 838839[CrossRef][ISI][Medline]
- Celik B, Shapiro R, Vats A, Randhawa PS. Polyomavirus allograft nephropathy: sequential assessment of histologic viral loads, tubulitis, and graft function following changes in immunosuppression. Am J Transplant 2003; 3: 13781382[CrossRef][ISI][Medline]
Received for publication: 3. 3.05
Accepted in revised form: 21. 4.05