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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2014  |  Volume : 25  |  Issue : 2  |  Page : 285-293
Occurrence of the polyomavirus among kidney transplant recipients: A single-center study


1 Department of Internal Medicine (Nephrology Unit), Faculty of Medicine, Alexandria University, Alexandria, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
3 Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt

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Date of Web Publication11-Mar-2014
 

   Abstract 

Polyoma virus-associated nephropathy is an increasingly recognized cause of graft dysfunction among kidney transplant recipients and could be the result of use of potent immunosuppression following transplantation. Because there is no safe and effective anti-viral therapy available presently, screening-based prevention and pre-emptive strategy are recommended. This study, which was conducted at the Nephrology Unit, Internal Medicine Department, Alexandria University, consisted of two phases: Phase 1 was a cross-sectional study and phase 2 was a 6-month follow-up study only for polyoma virus-positive cases. Phase 1 included 75 renal allograft recipients from living donors. Urine cytology for decoy cells and quantitative real-time blood polymerase chain reaction (PCR) for the BK virus (BKV) were performed on all the study patients. Renal biopsy was performed only in patients with deteriorating renal function associated with positive urine cytology. Patients who showed positive urine cytology for decoy cells and/or positive quantitative BKV PCR assay were followed-up for six months. During follow-up, the serum creatinine level, with or without urine cytology for decoy cells, and BKV PCR viral load assay were performed. Among the 75 kidney transplant recipients studied, eight were positive for decoy cells (11%), three showed viremia by quantitative PCR for BKV (4.1%), while two others showed nephropathy (2.7%) in the form of tubulointerstitial nephritis with intra-nuclear inclusions in the tubular cells. Cases with stable renal function and positive decoy cells or viremia cleared the virus spontaneously during follow-up without any intervention. Only one case with biopsyproven nephropathy and deteriorating graft function, with undetectable BKV in blood, lost the graft while another case with viremia died during follow-up due to septicemia. Our study suggests that polyoma virus should be considered as a cause of nephropathy in renal transplant recipients. Further research is required to understand this entity better.

How to cite this article:
Abdelsalam NF, Hashad DI, Salem MA, El-Wakil HS, Adam AG. Occurrence of the polyomavirus among kidney transplant recipients: A single-center study. Saudi J Kidney Dis Transpl 2014;25:285-93

How to cite this URL:
Abdelsalam NF, Hashad DI, Salem MA, El-Wakil HS, Adam AG. Occurrence of the polyomavirus among kidney transplant recipients: A single-center study. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2019 Nov 19];25:285-93. Available from: http://www.sjkdt.org/text.asp?2014/25/2/285/128509

   Introduction Top


The BK virus (BKV) and the JC virus, the two classical human polyoma viruses, were concurrently reported in 1971 and named with the initials of the patients from whom they were first isolated. [1]

The last decade has witnessed the introduction of several potent immunosuppressive agents in the field of transplant medicine. Infection with the BKV has emerged as an important complication of immunosuppres-sion, resulting in allograft loss after kidney transplantation, because it negatively influences graft outcome. [2]

The BKV is the causative agent of polyoma virus-associated nephropathy, which occurs when the BKV reactivates from a latent state due to immunosuppressive therapy, after renal transplantation. Viral replication begins early after transplantation and progresses through detectable stages: Viruria followed by viremia and finally nephropathy. [3],[4]

Early detection of BKV infection provides an opportunity for pre-emptive treatment. [5] Urine cytology for decoy cells, which are virally infected urothelial cells, and demonstration of viruria or viremia with polymerase chain reaction (PCR) for BKV DNA are common screening tools. [6] Urine cytology, serum PCR and allograft biopsy have been used to assess the reactivation of BKV. [7]

There are different guidelines for screening of the BKV; one guideline suggests using urine screening for decoy cells by various techniques as well as urine PCR. [8] Another one suggests screening of urine or plasma by PCR. [9] The last one suggests screening of plasma PCR from the beginning, monthly initially for the first 3-6 months followed by evaluation every three months till the 12 th month [Table 1]. [10] Renal allograft biopsy remains the gold standard for diagnosing BKV nephropathy. [11]
Table 1: Comparison of major group guidelines regarding screening for BK virus.

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In the absence of safe, specific and efficacious anti-viral agents, the current mainstay of intervention resides in judicious reduction of the immunosuppression, similar to the management of Cytomegalovirus infection in the era before ganciclovir. Close monitoring for rejection after reduction of immunosuppression is warranted. [12]


   Materials and Methods Top


The study comprised of two phases: Phase 1 was a cross-sectional study involving 75 renal allograft recipients and phase 2 was a follow-up study of patients who were positive for BKV infection. Follow-up was at an interval of 1-3 months, for up to six months. The study was conducted at the Nephrology Unit, Internal Medicine Department, Faculty of Medicine, Alexandria University.

The inclusion criteria were the following:

  1. Adult renal allograft recipients,

    Patients who received either calcineurin inhibitor-based protocol (cyclosporine or tacrolimus) or mammalian target of rapamycin inhibitor-based protocol (sirolimus or everolimus), with or without known induction therapy.


The exclusion criteria included the following:

  1. Pediatric transplant recipients,
  2. Cadaveric donor kidney transplant recipients.


All the study patients were subjected to full history taking, complete clinical examination and measurement of complete blood count (CBC), urea, creatinine, estimated glomerular filtration rate (eGFR) by the Cockroft-Gault formula, modification of diet in renal disease and chronic kidney disease-epidemiology collaboration formulas, alanine amino transferase (ALT), aspartate amino transferase (AST), total cholesterol and triglycerides. Urine cytology was analyzed to look for decoy cells as a possible marker of BKV replication. [13] The BK viral load in blood was quantified using real-time PCR. [14] Allograft biopsy was performed in cases with viremia and/or positive decoy cells, associated with renal dysfunction.

In phase 2, cases who showed positive urine cytology for decoy cells and/or detectable viral load by quantitative BKV PCR assay were followed-up. The follow-up was at 1-3-month interval, whenever possible, for up to six months. During each follow-up, the serum creatinine level was measured, urine was assessed for cytology to look for decoy cells and BKV PCR viral load assay was also performed.

Accordingly, the study population was divided into two groups:

  1. Group 1 included patients who were negative for decoy cells in urine and had undetectable BKV load in blood.
  2. Group 2 included patients who were positive for decoy cells and/or viremia and/or nephropathy.



   Statistical Analysis Top


Data were analyzed using SPSS software version 15. Entered data were checked for accuracy and then for normality. The following statistical tests were used: (a) Fisher's Exact and Monte Carlo tests as non-parametric tests of significance for one-way comparison between two qualitative samples, (b) Mann- Whitney test was used as a non-parametric test of significance for one-way comparison between means of two samples, when the independent t-test was not appropriate, (c) multi-variate logistic regression analysis of the factors associated with polyoma virus reactivation, (d) Spearman's rank correlation coefficient was used as a non-parametric measure of the mutual relationship between two not-normally distributed quantitative or ordinal variables and (e) Kaplan-Meier survival analysis was used to assess the mean time of recovery from polyoma virus reactivation and the reactivation-free survival.

Statistical significance was considered at a P-value of <0.05.


   Results Top


The demographic and clinical data of the whole group and the two sub-groups are shown in [Table 2]. Routine laboratory data of the whole group and the two sub-groups are shown in [Table 3].
Table 2: Demographic and clinical data of the study patients and the two sub-groups.

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Table 3: Routine laboratory data of the study patients and the two sub-groups.

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Urine cytology for decoy cells was positive in eight out of the 73 cases (11%) in whom it was tested [Figure 1]. In two cases, the test could not be performed because the cells in the urine smear had degenerated (more than 8 h concentration) and the patients refused repeating the test. The BKV load was detected by PCR in three of the 74 patients in whom it was tested (4.1%). In one case, the test could not be performed for logistic reasons.
Figure 1. Urine cytology: (A and B) groups of desquamated urothelial cells; some of them have nuclear inclusions compressing nuclear chromatin outside, (C and D) desquamated tubular cells showing intranuclear inclusions compressing nuclear chromatin outside. PAP stain × 1000.

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Allograft biopsy was performed in two cases with associated impaired graft function; both showed intra-nuclear inclusions in the medullary renal tubules [Figure 2]. Thus, the prevalence of polyoma virus nephropathy, in our study, was 2.7%.
Figure 2. Renal allograft biopsy showing intra-nuclear inclusion bodies within the tubular epithelial cells, H&E × 400 and 1000, respectively.

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Exposure to more than one rejection episode paved the way for polyoma virus reactivation significantly (P = 0.012). Similarly, exposure to more than one dose of methylprednisolone pulse had a positive impact on viral reactivation significantly (P = 0.012). Additionally, there was a significant difference between the two studied sub-groups in the percentage of patients with immunosuppressive drug levels above the target range (P = 0.004). Multi-variate logistic regression analysis examined the relationship between the number of transplantations, duration since transplantation, number of acute rejection episodes and the levels of the immunosuppressive drugs as different variables and the reactivation of polyoma virus among kidney transplant recipients.

The results revealed that high levels of immunosuppressive drugs were significantly associated with polyoma virus reactivation; thus, when the level of the immunosuppressive drug was above the target range, the risk of polyoma virus reactivation was increased by 12.71 times. (OR = 12.710, P = 0.008, CI: 1.963- 82.289).

However, the number of transplantations, duration since transplantation and number of acute rejection episodes were not significant predictors of polyoma virus reactivation in this study (P = 0.841, 0.256 and 0.498 respectively).

Cases with stable renal function and positive decoy cells, with or without viremia, cleared the virus spontaneously during the follow-up period without the need of intervention. One case with biopsy-proven nephropathy and deteriorating graft function and undetectable viral load of BKV in the blood lost the graft. One case of viremia died due to septicemia before allograft biopsy could be performed [Table 4]
Table 4: Specific findings of group II during presentation and after follow-up.

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Kaplan-Meier analysis demonstrated that the mean time to recovery from polyoma virus reactivation was 120.8 ± 31.302 days while the reactivation-free survival was 77.8%.


   Discussion Top


The emergence of polyoma virus nephropathy has coincided with the use of new potent immunosuppressive medications. [15] It is usually associated with the BKV, affects up to 8% of recipients and frequently results in allograft loss or permanent dysfunction. [6]

All patients with BKV nephropathy show evidence of viral activation, but not all patients with signs of viral activation have features of BKV nephropathy. [16]

In the current study, which included 75 renal allograft recipients, reactivation of the polyoma virus occurred in 10 of a total of 75 renal allograft recipients, yielding a reactivation rate of 13%.

Hirsch et al [11] found that the rate of reactivation of BKV varied from 10-68% in renal transplant recipients. This matches the results of our study and also explains why the conditions related to BKV reactivation are gaining important clinical significance in kidney transplant centers worldwide.

Furthermore, in this study, the rate of occurrence of decoy cells as a marker of viral replication was 11%, while the rates of occurrence of BK viremia and nephropathy were 4.1% and 2.7%, respectively.

These results are similar to some other reports; Chakrapol et al [12] found that decoy cells were detected in 12% of renal transplant recipients while Brennan et al [4] detected BK viremia in <15% of renal transplant recipients, a finding superior to decoy cell screening. Nevertheless, decoy cell shedding can be detected prior to the development of viremia. Furthermore, Dharnidharka et al, [17] in a single-center study and registry data, reported that approximately 1-10% of all renal transplant recipients develop polyoma virus-associated nephropathy.

These results match the results of our study regarding decoy cells and nephropathy; however, we noticed viremia occurring less frequently than other published reports. This may be explained by the observation that BKV viruria precedes BKV viremia, and it is a prerequisite for histologically proven BKV nephropathy because the viral replication within the graft finally leads from viruria to viremia. [18] Because we screened kidney transplant recipients for decoy cells and quantitative BKV PCR at the same time, this might have caused the discrepancy in the occurrence of BK viremia in our patients.

In our study, there was a significantly high trough level of the immunosuppressive drugs, above the target range, in the group that showed reactivation of polyoma virus. On the contrary, there was no significant effect of the immunosuppressive protocol or a particular immunosuppressive agent on viral reactivation. The reactivation group was exposed to a higher degree of immunosuppression than the negative group, which supports the belief that it may not be the type but rather the intensity of immunosuppression that predisposes to BKV nephropathy.

These findings are in accordance with those of Bressollette et al, [19] who found a correlation between the incidence of BKV infection in renal transplant recipients and the degree of immunosuppression, without any effect of either a specific drug or any combination. The intensity of immunosuppression rather than the immunosuppressive agents most likely accounts for the inability of the transplant recipient's immune system to control the viral infection. [20]

In concordance with this observation, our cohort showed that the number of acute rejection episodes was significantly greater in the reactivation group in comparison with the negative group. Similarly, Perez-Torres et al [21] found that patients with BKV had a significantly higher number of graft rejection episodes. It has been well documented that BKV nephropathy is associated with high rates of rejection, and that both processes can co-exist in the renal allograft. On the other hand, the difficulty in distinguishing acute rejection from BKV nephropathy, particularly in advanced cases, may lead to over-estimation of the frequency of rejection in these patients.

We also noticed that administration of corticosteroid pulses, more than one pulse, was significantly more frequent in the reactivation group in comparison with the negative group. This was similar to the findings of Randhawa et al, [11] who identified anti-rejection corticosteroid bolus as a risk factor for the enhancement of the pathogenesis of BKV.

On studying the other risk factors for BKV infection, it was found that sex, age, underlying renal disease, number of renal transplants, duration since transplantation, donor characteristics and serum creatinine level at the time of presentation were not identified as risk factors among our cohort.

Similarly, Wu et al [5] studied the effect of age, gender, time between transplantation and BKV screening, underlying diseases, immunosuppressive regimen and serum creatinine level at the time of screening on BKV reactivation. They reported that none of these factors were uniformly associated with viral reactivation.

In contrast, Emilo Ramos et al [22] found that patients with BKV nephropathy were older and there was a male predominance; but, they did not find any significant association with other factors such as living donor, mean HLA mismatch, delayed graft function, acute rejection, immunosuppressive drugs or history of diabetes.

Ziedina et al [23] identified re-transplantation as a risk factor for reactivation, but they did not identify age and sex as risk factors. Re-transplantation being a risk factor is consistent with the hypothesis that the overall level of immunosuppression is responsible for BKV reactivation. [24] In our study, there was only one case with re-transplantation, and this patient did not have BKV reactivation.


   Conclusion Top


The intensity of immunosuppression rather than the immunosuppressive agents used are likely to account for polyoma virus reactivation. Recent graft rejection with incomplete response to anti-rejection therapy should raise the suspicion of PVAN. Urine cytology for decoy cells is a good screening test. However, decoy cells are not entirely sensitive or specific for BKV infection. Also, it does not correlate with biopsy-verified BKV-induced interstitial nephritis. Viremia, detected by quantitative PCR in blood, correlates closely with allograft involvement and helps in early diagnosis, determining clinical response to antiviral therapy and monitoring for relapse. Allograft biopsy remains the gold standard for diagnosing BKV nephropathy. Prevention, based on a screening and pre-emptive strategy, is superior to an approach that relies upon therapy of established disease. Judicious reduction of immunosuppression is the current mainstay of intervention due to absence of safe, specific and efficacious anti-viral drugs.

 
   References Top

1.Gardner SD, Field AM, Coleman DV, Hulme B. New human papovavirus (B.K.) isolated from urine after renal transplantation. Lancet 1971;1:1253-7.  Back to cited text no. 1
    
2.Agha I, Brennan DC. Polyoma viruses and Human Diseases. Adv Exp Med Biol 2006; 577:174-84.  Back to cited text no. 2
    
3.Reploeg MD, Storch GA, Clifford DB. BK virus: A clinical review. Clin Infect Dis 2001; 33:191-202.  Back to cited text no. 3
    
4.Brennan DC, Agha I, Bohl DL, et al. Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction. Am J Transplant 2005;5:582-94.  Back to cited text no. 4
    
5.Wu SW, Chang HR, Hsieh MC, Chiou HL, Lin CC, Lian JD. Early diagnosis of polyomavirus type BK infection in tailoring immunosuppression for kidney transplant patients: Screening with urine qualitative polymerase chain reaction assay. Transplant Proc 2008;40:2389-91.  Back to cited text no. 5
    
6.Hirsch HH, Knowles W, Dickenmann M, et al. Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med 2002;347:488-96.  Back to cited text no. 6
    
7.Mayr M, Nickeleit V, Hirsch HH, Dickenmann M, Mihatsch MJ, Steiger J. Polyomavirus BK nephropathy in a kidney transplant recipient: Critical issues of diagnosis and management. Am J Kidney Dis 2001;38:354-65.  Back to cited text no. 7
    
8.Hirsch HH, Brennan DC, Drachenberg CB, et al. Polyomavirus-associated nephropathy in renal transplantation: Interdisciplinary analyses and recommendations. Transplantation 2005; 79:1277-86.  Back to cited text no. 8
    
9.Hirsch HH, Randhawa P. BK virus in solid organ transplant recipients. Am J Transplant 2009;9(Suppl 4):S136-46.  Back to cited text no. 9
    
10.Kidney Disease Improving Global Outcomes (KDIGO) Transplant Work Group KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9(Suppl 3):S1-155.  Back to cited text no. 10
    
11.Randhawa P, Ho A, Shapiro R, et al. Correlates of quantitative measurement of BK polyomavirus (BKV) DNA with clinical course of BKV infection in renal transplant patients. J Clin Microbiol 2004;2:1176-80.  Back to cited text no. 11
    
12.Sriaroona C, Greene JN, Vincent AL, Tucci VT, Kharfan-Dabaja MA, Sandin R. BK virus: Microbiology, epidemiology, pathogenesis, clinical manifestations and treatment. Asian Biomed 2010;4:3-18.  Back to cited text no. 12
    
13.Kipp BR, Sebo TJ, Griffin MD, Ihrke JM, Halling KC. Analysis of polyomavirus-infected renal transplant. Am J Clin Pathol 2005; 124:854-61.  Back to cited text no. 13
    
14.Wittwer C, Kusukawa N. Nucleic acid technique. In: Burtis CA, Ahwood ER, Bruns DE, eds. Teitz Text Book of Clinical Chemistry and Molecular Diagnostics, 4 th ed. Vol. 3, Philadelphia: Elsevier Saunders; 2006. p. 1407-49.  Back to cited text no. 14
    
15.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. 15
    
16.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. 16
    
17.Dharnidharka VR, Cherikh WS, Abbott KC. An OPTN analysis of national registry data on treatment of BK virus allograft nephropathy in the United States. Transplantation 2009;87: 1019-26.  Back to cited text no. 17
    
18.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. 18
    
19.Bressollette-Bodin C, Coste-Burel M, Hourmant M, Sebille V, Andre-Garnier E, Imbert-Marcille BM. A prospective longitudinal study of BK virus infection in 104 renal transplant recipients. Am J Transplant 2005;5:1926-33.  Back to cited text no. 19
    
20.Funk GA, Gosert R, Comoli P, Ginevri F, Hirsch H. Polyomavirus BK replication dynamics in vivo and in silico to predict cytopathology and viral clearance in kidney transplants. Am J Transplant 2008;8:2368-77.  Back to cited text no. 20
    
21.Perez-Torres D, Bertran-Pasarell J, Santiago-Delpin E, et al. Factors and outcome in BK virus nephropathy in a Hispanic kidney transplant population. Transpl Infect Dis 2010;12: 16-22.  Back to cited text no. 21
    
22.Ramos E, Drachenberg CB, Papadimitriou JC, et al. Clinical course of polyoma virus nephropathy in 67 renal transplant patients. J Am Soc Nephrol 2002;13:2145-51.  Back to cited text no. 22
    
23.Ziedina I, Folkmane I, Chapenko S, et al. Reactivation of BK Virus in the Early Period After Kidney Transplantation. Transplant Proc 2009;41:766-8.  Back to cited text no. 23
    
24.Blanckaert K, De Vriese S. Current recommendations for diagnosis and management of polyoma BK virus nephropaty in renal transplant recipients. Nephrol Dial Transplant 2006; 21:3364-7.  Back to cited text no. 24
    

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Correspondence Address:
Hala S El-Wakil
Department of Internal Medicine (Nephrology Unit), Faculty of Medicine, Alexandria University, Alexandria
Egypt
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DOI: 10.4103/1319-2442.128509

PMID: 24625993

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