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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2005  |  Volume : 16  |  Issue : 4  |  Page : 514-519
Polyomavirus Nephropathy


1 Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Maryland, USA
2 Department of Pathology, University of Maryland School of Medicine, Maryland, USA

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   Abstract 

We have seen the re-emergence of a virus, normally latent in the urinary tract, which becomes activated in renal transplant patients due to potent immunosuppression. Polyomavirus reactivates within the allograft kidney, causing renal dysfunction and graft loss in 40 to70% of patients with overt renal dysfunction and histologically proven Polyomavirus nephropathy. More research and data are needed to further elucidate the pathogenicity of the virus, and to find an effective antiviral agent.

How to cite this article:
Ramos E, Drachenberg C. Polyomavirus Nephropathy. Saudi J Kidney Dis Transpl 2005;16:514-9

How to cite this URL:
Ramos E, Drachenberg C. Polyomavirus Nephropathy. Saudi J Kidney Dis Transpl [serial online] 2005 [cited 2019 Jul 21];16:514-9. Available from: http://www.sjkdt.org/text.asp?2005/16/4/514/32843

   Introduction Top


Polyomaviruses are the group of viruses which affect mostly vertebrates, including humans. There is a subgroup of Polyomaviruses that are pathogens for humans, including JC, BK, and SV-40. [1] The BK virus was named after the first patient in whom it was discovered at St. Mary's Hospital in London in the early 70s. [2] It is a double-stranded DNA virus that is 40 to 45 nm in diameter. JC was also named after the first patient in whom it was discovered, who had progressive multifocal leukoencephalopathy or PML. [3] SV-40 is a simian virus that has quite a few analogies with BK and JC, but mainly infects monkeys. [4] The BK genome has 3 regions; an early region, consisting mainly of the T-large antigen and the t-antigen. In addition, it has a middle region, which is the regulatory region of the virus and, finally, a late region, which is mainly composed of the capsids or the semi-envelope of the virus, which includes VP-1, VP-2 and VP-3. [5]

After the virus enters the epithelial cell by endocytosis, the BK virus genome moves to the nucleus. Early expression and replication of the BK virus mini-chromosome is needed before late gene expression ensues and virions are assembled in the nucleus. The virions then are shed into the urinary space, and appear in the urine in the form of decoy cells. Repli­cation continues within the cell and infects other cells around the original infected one. [6]


   Epidemiology Top


BK and JC viruses are very ubiquitous. Primary infection occurs between the age of 4 and 6, usually manifested by a small episode of coryza. [7]

Prevalence is between 65 and 100 per cent of the adult population, depending upon age group and geographical location. [8] After the primary infection, the virus goes latent and stays in the renal-urinary tract within the cortex and medulla of the kidney, the ureter and the bladder. [9] Also, the virus has been demonstrated in the prostate. [9] Another trans­mission of the BK virus is mainly through the respiratory route, via aerosolized particles. 10 It has also been shown to be the oral-fecal route, as BK has been found in sewage. [1] Other potential routes of transmission include blood transfusion and organ transplantation, particularly renal transplantation.


   Risk Factors Top


Reactivation of the virus occurs mainly when the center of immunity is lowered, as in the case of pregnancy. About 3% of pregnant females shed the virus in the urine during the third trimester of the pregnancy. [13] Fortunately, however, the virus clears in the 2 weeks post partum, and there are no clinical consequences. Reactivation also occurs in patients who are immunosuppressed, such as renal organ transplant patients, patients with uncontrolled diabetes and patients with AIDS. [1]


   Historic Background Top


The first case of human polyomavirus in a renal transplant patient was described in 1971 at St. Mary's Hospital in London by Dr. Sylvia Gardner, in a Sudanese patient who had a living related transplant from his brother, who presented with renal dysfunction secondary to ureteral stenosis. The patient was shedding decoy cells in the urine. In addition, a biopsy of the ureteral stenosis demonstrated histologically the presence of BK virus within the epithelial cells of the ureter. [2] In 1978, the pathogenicity of BK and JC remained unclear. However, during the late 70s, several studies confirmed the patho­genicity of Polyomavirus in renal transplant patients. [1] In the 1980s, there was very little literature about BK, and the virus seemed to have been forgotten. Interestingly, from 1995 to the present, there has been a marked increase in the number of reported cases of Polyomavirus nephropathy. This is most likely due to the advent of more immuno­suppressive medications, which include Myco­phenolate Mofetil, Tacrolimus, Sirolimus, Cyclosporine and the IR-2 antibodies. [1]


   Clinical Presentation Top


The clinical presentation occurs in the form of asymptomatic viruria, or the presence of decoy cells in the urine, which can be seen in about 65% of renal transplant patients or in pregnant patients as described earlier. It can also present clinically in the form of white cells in the urine, since Polyomavirus nephro­pathy is usually interstitial nephritis. It can, of course, present with renal dysfunction. It can also present with ureteral stenosis, as in the first case described and in patients with bone marrow transplantation, it can present as hemorrhagic cystitis.


   Diagnosis Top


At the present time, because we do not have very good markers for the disease.The obser­vation of viral cytopathic changes from renal biopsy with confirmation by immunohisto­chemistry using SV40 and electron microscopy are considered to be the only useful tools for the diagnosis of Polyomavirus nephropathy. In addition, urine cytology, plasma BK virus poly chain reaction (PCR) is also needed. [1],[10],[11]

At the latent stage, as seen in immunocom­petent patients and pregnant women, the virus can be detected by tissue PCR in the kidney. However, at this stage, there is no viruria, i.e., there is absence of decoy cells in the urine, and the urine is negative for BK PCR. At the same time, there is no viremia and no clinical significance; in other words the patient has normal renal function. [1] The second stage is low-level viral replication. This stage is common in immunosuppressed patients and may occur rarely in healthy individuals like pregnant women as discussed previously. [1] It occurs in between 20 and 65% of renal transplant patients. [1] The viruria is usually transient; there is no evidence of viremia by plasma PCR, and again there is no clinical significance, which means that the patient's renal function remains normal.

The third stage is characterized by high repli­cation with tissue destruction. This is the classical Polyomavirus-associated nephropathy, which occurs in 5 to 10% of transplant patients. In this case, you can see significant viremia by quantitative PCR, along with the presence of renal dysfunction, either moderate or severe, depending upon the amount of tissue destruction present. The eventual progression of the virus is from transient viruria to persistent viruria to significant viremia and renal dysfunction with tissue damage. [10],[11]


   Histopathology Top


The histological diagnosis of Polyomavirus nephropathy (PVN) rests on the identification of PV cytopathic changes. These are confirmed by ancillary methods, the most commonly used being immunohistochemical stains. Typically an antibody against the SV40 large T antigen is applied which cross reacts with the BK and the JC viruses. [1] PVN is always associated with shedding of virions and viral proteins in the urine. This can be demonstrated with the evaluation of urine cytology to demonstrate "decoy cells" or by quantitative PCR studies.

Viruria is a manifestation of viral replication in the urinary tract and it is seen not only in the allograft nephropathy but is also chara­cteristic of the primary infection with the BK and JC viruses. [1] Renal parenchymal injury due to PVN is typically associated with increasing levels of BK viremia. "Spillage" of viral components into the blood stream is believed to be proportional to the degree of tissue damage; however, this has not been conclusively demonstrated. [1] The presence of significant inflammation and tubulo-inter­stitial atrophy in the first biopsy with PVN is associated with worsened outcomes in comparison to patients diagnosed early on. Histological patterns of PVN have been defined by increasing degrees of fibrosis and tubulo­interstitial atrophy. The latter changes indicate renal scarring and if diffuse portend a bad outcome, particularly in patients with concurrent increase in creatinine. [13] Accurate diagnosis of PVN can be best achieved by a combination of a renal biopsy with determination of viruria and viremia. Successful outcome with clearance of the infection is defined by disappearance of viral cytopathic changes in biopsy with progressive decrease and eventual disappearance of viruria and viremia. [14]


   Algorithm for Diagnosis and Treatment of Polyomavirus Nephropathy Top


At the University of Maryland Hospital, per the algorithms used, depicted in [Figure - 1], we check all renal transplant patients for decoy cells at months 1, 2, 3, 6, 9, and 12 following transplantation. If urine cytology is positive, we repeat the cytology in a month and, if the urine cytology is positive a second time, we do quantitative plasma PCR. At the same time, we do a renal biopsy, even if renal function is normal. We also do a kidney biopsy if the plasma PCR is greater than 10,000 copies/ml. There are several possibilities that we see in the biopsy. In defined Polyomavirus nephro­pathy, we reduce immunosuppression, which means that we decrease the tacrolimus to a level of 6 and 8 mg/ml, cyclosporine to a level of 65 to 100 mg/ml or sirolimus to a level of 8 to 10 mg/ml. In addition, we decrease the MMF by one half, and if the urine remains positive after one month of decreased immunosuppression, we stop the mycophenolate mofetil (MMF). At the same time, we follow these patients very closely, in that a check of serum chemistry including renal function, calcineurin inhibitor and Rapamune levels weekly for 1 month, bi-weekly for two months, and monthly thereafter. Also, during that period, we decrease immunosuppression appropriately according to target levels ofcalcineurin inhibitors and Rapamune. If there is any evidence of renal dysfunction not explained otherwise, we perform a second biopsy to rule out acute rejection. [13],[14] When we see an association of PVN and acute rejection, which happens in about 15% of cases, we usually treat rejection with intravenous steroids for three days, after which the prednisone is tapered, and then we reduce immunosuppression as we do in patients with PVN. [13] In addition to decreased immunosuppression, there are several agents, which have been known to have anti­BK properties in vitro, including cidofovir, lefleuramide, diquinolone and a new agent, FK-778, which is under investigation at the present time. These agents have not been approved so far by the FDA in the United States. However, they seem to clear the viruria and viremia in these patients. If fibrosis is present, and the patient has moderate to severe renal failure, they progress to end-stage renal disease, even with the addition of these antiviral agents.


   Retransplantation in Patients Who Lost Their Graft to PVN Top


One of the difficult clinical questions that we face is what to do with patients who have lost their kidney to PVN. Do we condemn them to return to dialysis, or is it safe to re­transplant these patients without recurrence of the virus? In a recent paper, we published 10 cases of patients who lost their allograft to PVN and were re-transplanted. [15] These cases were collected from five transplant centers in the United States. Interestingly, seven of these 10 patients did have nephroureterectomies, whereas 3 did not. Nephroureterectomy was performed in the hope of completely eliminating the recurrence of the nephropathy. After the second transplant, all patients were re-started on the same immunosuppressive medication that they were given following the first trans­plant without decreasing immunosuppression. Only one patient had a recurrence of BK nephropathy. This patient did have a nephro­ureterectomy prior to the second transplant.

Although the number of cases is very small, we can conclude that neither nephrouretere­ctomy of the first allograft nor the selection of a new or different immunosuppressive agent appeared to influence the risk of recurrence of Polyomavirus nephropathy. It is important to stop all immunosuppressive medications at the time that the kidney fails from Polyoma­virus nephropathy and keep the patient off immunosuppression for 2 months. Also, it is important at the time of the second transplant that the patient has a negative urine cytology and negative plasma PCR. If those conditions are met, the patient can be safely re-transplanted without performing a nephroureterectomy.

In summary, we have seen the re-emergence of a virus which has been latent in the urinary tract system, and because of more potent immunosuppressive medication, the virus reactivates within the allograft kidney, causing renal dysfunction and graft loss in 40 to 70% of patients with overt renal dysfunction and histologically proven Polyomavirus nephropathy. More research and data are needed to further elucidate the pathogenicity of the virus, and to find an effective antiviral agent.

 
   References Top

1.Hirsch HH, Steiger J. Polyomavirus BK. Lancet Infect Dis 2003;3:611-23.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Gardner SD, Field AM, Coleman DV, Hulme B. New human papovavirus (B.K) isolated from urine after renal transplantation. Lancet 1971;1:1253.  Back to cited text no. 2    
3.Binet I, Nickeleit V, Hirsch HH, et al. Polyomavirus disease under new immunosuppressive drugs: a cause of renal graft dysfunction and graft loss. Transplantation 1999;67:918-22.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]
4.Shah KV, Daniel R, Warszawski R. High prevalence of antibodies to BK virus, an SV40-related papovavirus, in residents of Maryland. J Infect Dis 1973;128:784-7.  Back to cited text no. 4    
5.Knowles WA. The epidemiology of BK virus and the occurrence of antigenic and genomic subtypes. In: Khalili K, Stoner GI, eds. Human polyomaviruses: molecular and clinical perspectives. New York: Wiley­Liss 2001;527-59.  Back to cited text no. 5    
6.Chesters PM, Heritage J, McCance DJ. Persistence of DNA sequences of BK virus and JC virus in normal human tissues and in diseased tissues. J Infect Dis 1983;147:676-84.  Back to cited text no. 6  [PUBMED]  
7.Goudsmit J, Wertheim-van Dillen P, van Strien A, van der Noordaa H. The Role of BK virus in acute respiratory tract disease and the presence of BKV DNA in tonsils. J Med Virol 1982;10:91-9.  Back to cited text no. 7    
8.Sundsfjord A, Spein AR, Lucht E, Flaegstad T, Seternes OM, Traavik T. Detection of BK virus DNA in nasopharyngeal aspirates from children with respiratory infections but not in saliva from immunodeficient and immunocompetent adult patients. J Clin Microbiol 1994;32:1390-4.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]
9.Andrews CA, Shah KV, Daniel RW, Hirsch MS, Rubin RH. A serological investigation of BK virus and JC virus infections in recipients of renal allografts. J Infect Dis 1988;158:176-81.  Back to cited text no. 9  [PUBMED]  
10.Drachenberg CB, Papadimitriou JC, Hirsch HH, et al. Histological patterns of polyomavirus nephropathy: correlation with graft outcome and viral load. Am J Transpl 2004;4:2082-92.  Back to cited text no. 10    
11.Hirsch HH, Knowles W, Dickenmann M, et al. Prospective study of polyomavirus type BK replication and nephropathy in renal­transplant recipients. N Engl J Med. 2002; 347:488-496.  Back to cited text no. 11    
12.Hirsch HH, Brennan DC, Drachenberg CB, et al. Polyomavirus-associated nephropathy in renal transplantation: Interdisciplinary analysis and recommendations. Transplantation 2005;79:1277-86.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]
13.Ramos E, Drachenberg CB, Portocarrero M, et al. BK virus nephropathy diagnosis and treatment: experience at the University of Maryland Renal Transplant Program. Clin Transpl 2002;143-53.  Back to cited text no. 13    
14.Ramos ER, Drachenberg CB, Papadimitriou JC, Wali R, Cangro C, Weir MR. Impact of prospective urine cytology on graft function (GF) for earlier diagnosis of polyoma virus nephropathy. J Am Soc Nephrol 2003;13:378A.  Back to cited text no. 14    
15.Ramos E, Vincenti F, Lu WX, et al. Retransplantation in patients with graft loss caused by polyoma virus nephropathy. Transplantation 2004;77:131-3.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]

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Correspondence Address:
Emilio Ramos
Department of Medicine, Division of Nephrology, University of Maryland School of Medicine
USA
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PMID: 18202506

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    Abstract
    Introduction
    Epidemiology
    Risk Factors
    Historic Background
    Clinical Present...
    Diagnosis
    Histopathology
    Algorithm for Di...
    Retransplantatio...
    References
    Article Figures
 

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