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Volume: 9 Issue: 3 June 2011

FULL TEXT

ARTICLE

Prospective Study of Posttransplant Polyomavirus Infection in Renal Transplant Recipients

Objectives: The BK virus is the most common pathogen in renal transplant recipients. Limited information is available regarding JC virus or Simian virus infections in renal transplant recipients. This prospective study sought to investigate the rate of BK virus, JC virus, and Simian virus 40 infections and their influence on allograft function in the early stages after surgery.

Materials and Methods: In total, 50 renal transplant recipients and 20 healthy blood donors were studied. The BK virus, the JC virus, and the Simian virus 40 were detected by nested qualitative polymerase chain reaction assays in urine and plasma. The difference of glomerular filtration rate among BK virus-infected, JC virus-infected, and uninfected patients was compared using the Kruskal-Wallis test.

Results: The polyomavirus viruria was detected in 46% of renal transplant recipients (4% of the BK virus and 42% of the JC virus viruria) and 10% of the healthy blood donors (5% for the BK virus and the JC virus viruria). No polyomavirus viremia was detected. No difference of glomerular filtration rate was found among the 3 groups (X2 = 0.228; P = .892).

Conclusions: Polyomavirus infections are not uncommon, and the incidence of JC virus infection is much higher in renal transplant recipients than it is in BK virus. Neither BK virus nor JC virus infections appeared to influence graft function in the early stages after surgery.


Key words : Kidney transplant, Infections, BK virus, JC virus, Simian virus 40

Introduction

Polyomavirus belongs to the family Polyomavirus, which also includes the BK virus, the JC virus, and the Simian virus 40. The BK virus and the JC virus infections are ubiquitous, with a seroprevalence in 90% of adults.1 After initial childhood infections in healthy individuals, Polyomavirus may persist in the kidney epithelium, the genitourinary tract epithelium, and/or lymphocytes.2 It may be reactivated in immunocompromised or immunosuppressed individuals, such as those with HIV3 or those who have undergone a transplant.4 The BK virus is the most common pathogen in renal transplant recipients, and BK virus-associated Polyomavirus nephropathy is one of the most significant causes of graft dysfunction and loss in renal transplant recipients.5 The JC virus is more often associated with progressive multifocal leukoencephalopathy in AIDS patients. Only limited information is available regarding the JC or Simian virus 40 infections in renal transplant recipients and their effect on allograft function and pathologic changes. Recent studies5, 6 reported that the JC virus viruria exists in 22% of renal transplant recipients and could cause graft dysfunction and interstitial nephropathy. Additionally, the Simian virus 40 has been detected in renal transplant patients.7, 8 This prospective study sought to investigate the rate of BK virus infection and the incidence of JC-virus and Simian-virus–40 infection in renal transplant recipients and study their influence on allograft function during the first 3 months after surgery.

Materials and Methods

Patients and samples
In total, 50 adult renal transplant recipients (35 males, 15 females; mean age, 37.10 ± 11.633 years) from 2008 at our hospital were enrolled in this prospective study. No specific screening was used to allow or prevent enrollment. All renal transplant recipients were followed from the date of transplant. Standard demographic data, such as age, sex, primary renal diseases, and use of immunosuppressive therapy were collected. Urine and plasma samples were collected once weekly in the first month, and twice in the second and third months after transplant. In total, 136 urine and 136 plasma samples were collected from 50 renal transplant recipients. Also, 20 urine and 20 plasma samples were collected from a group of 20 healthy blood donors (10 men and 10 women; mean age, 37.50 ± 7.695 years). Specimens were stored at 70ºC until processed.

At each visit, data on hepatitis B virus infection, hepatitis C virus infection, and serum creatinine were collected. Baseline immunosuppression was as follows: intraoperative and 2-day postoperative, methylprednisolone intravenous pulse therapy beginning on the third day of the triple-drug regimen (which commonly includes mycophenolate mofetil, prednisone, and cyclosporine or tacrolimus). Acute rejection was confirmed by a percutaneous core needle allograft biopsy, which was conducted for patients clinically suspected of having a rejection episode (including those patients with a rise in serum creatinine accompanied by clinical findings such as increased body temperature, decreased urine output, hematuria, proteinuria, hypertension, and graft pain/tenderness).9 When acute rejection occurred, methylprednisolone pulse therapy was the first choice; otherwise, OKT3 or antilymphocyte globulin was used.

Nested polymerase chain reaction for Polyomavirus DNA detection
Polyomavirus DNA was extracted from 150 µL of urine using the MagneSil Total DNA/RNA mini-Isolation System (Promega, Shanghai, China). Polyomavirus DNA detection was done with a nested polymerase chain reaction, using previously validated primers10 that amplified a conserved region of the T-antigen gene from the BK virus, the JC virus, and the Simian virus 40. For the first run, a total of 25 µL of polymerase chain reaction mixture containing 2 µL extracted DNA, 2.5 µL 10 × Ex Taq buffer (Takara), 2 µL dNTP mix, 0.25 µL (40 pmol/µL) PM1 + (primer), 0.25 µL (40 pmol/µL) PM1-(primer), 0.125 µL (0.625 U) Takara Ex Taq HS, and 18 µL distilled water was used.

Amplification conditions were as follows: 95ºC for 4 minutes; followed by 39 cycles at 94ºC for 30 seconds, 58ºC for 30 minutes, and 72ºC for 40 seconds; then 72ºC for 7 minutes. For the second run, a total of 25 µL of polymerase chain reaction mixture containing 2 µL of the first round polymerase chain reaction product, 2.5 µL 10 × Ex Taq buffer (Takara), 2 µL dNTP mix, 0.20 µL (40 pmol/µL) BK + (primer), 0.20 µL (40 pmol/µL) JC + (primer), 0.20 µL (40 pmol/µL) Simian virus 40 + (primer), 0.30 µL (40 pmol/µL) PM2-(primer), 0.15 µL (0.75 U) Takara Ex Taq HS, and 17.5 µL distilled water was used. Amplification conditions were identical to those of the first polymerase chain reaction round.

Each amplification used distilled water as a negative control and positive polymerase chain reaction products (353 bp for the BK virus, 189 bp for the JC virus,135 bp for the Simian virus 40) as positive controls (sequenced by ZeHeng Technology Co. Ltd., Shanghai, China). The polymerase chain reaction products were analyzed by electrophoresis on 1.5% agarose in 0.5 × TBE gels, stained with ethidium bromide, and visualized under ultraviolet light. Positive polymerase chain reaction products were sequenced by ZeHeng Technology Co. Ltd., Shanghai, China, and analyzed using BLAST software.

Nested polymerase chain reaction for Polyomavirus DNA detection in blood was performed on only the simultaneously collected plasma samples of patients with the BK virus or the JC virus viruria, including 40 blood samples from 23 patients; viremia is not likely to occur in the absence of viruria,11 and a blood polymerase chain reaction is only recommended in patients with Polyomavirus viruria.12

Qualitative polymerase chain reaction for Cytomegalovirus DNA detection
The cytomegalovirus DNA extractions, the polymerase chain reaction reaction system, and the amplification conditions were identical to those of the first run of Polyomavirus nested polymerase chain reaction, with the exception of the primers specific to the virus-conserved genome (UL83).13

Analytic sensitivity of the procedure
Before testing the urine samples, sensitivity of the complete procedure was calculated by amplifying serial dilutions of plasmids in 25 µL of distilled water. Conditions for extraction and amplification were the same as for the clinical samples, and all dilutions were assayed in triplicate.

Hepatitis B virus and hepatitis C virus detection
HBsAg, HBeAg, anti-HBs, anti-HBe, anti-HBc were collected for each patient during each posttransplant visit, which was detected regularly using commercially available test kits (Diagnostic kit for the Quantitative Detection of Hepatitis B) (SYM-BIO Life Science Co. Ltd., Suzhou, China) by the biochemical laboratory of our hospital. Hepatitis C virus-Ab was also collected and detected by the biochemical laboratory of our hospital using a diagnostic kit for antibody to hepatitis C virus (ELISA) (Beijing Wantai Biological Pharmacy Enterprise Co. Ltd., Beijing, China).

Renal function detection
Glomerular filtration rate is the optimal indicator of renal function.12, 14 A serum creatitine level was collected for each patient during each posttransplant visit, which was detected using creatinine reagent kit (enzymatic methods) (Shanghai Shensuo Unf Medical Diagnostic Articles Co. Ltd., China) by the biochemical laboratory of our hospital and then converted to a glomerular filtration rate according to the modified abbreviated Modification of Diet in Renal Disease equations suitable for Chinese.14 The difference of glomerular filtration rate among BK virus-infected, JC virus-infected and noninfected patients was compared.

Statistical analyses
Statistical analyses were performed with SPSS software for Windows (Statistical Product and Service Solutions, version 16.0, SSPS Inc, Chicago, IL, USA). Quantitative variables were expressed as mean values ± standard deviation (SD) for normally distributed data. These data were compared using the Kruskal-Wallis test. Qualitative variables were expressed as a percentage of positive results, and differences between these variables were evaluated using the chi-square or the Fisher exact test. All P values were based on a 2-tailed test of significance (P = .05).

Results

The rate of infection
Of 136 urine samples in renal transplant recipients and 20 urine samples in healthy blood donors, we found Polyomavirus in 40 (4 with the BK virus and 36 with the JC virus) and 4 (2 with the BK virus and 2 with the JC virus) urine samples. The positive polymerase chain reaction products were then sequenced by ZeHeng Technology Co. Ltd, Shanghai, China, and analyzed using BLAST software. We found the homology between the sequencing results of the positive polymerase chain reaction products and the objective gene sequencing of the BK virus and the JC virus DNA in the GenBank achieved 99%.

In 50 renal transplant recipients, Polyomavirus DNA was found in 23 patients (46%), 2 of which were infected with the BK virus (4%), and 21 patients with the JC virus (42%). Of 20 urine samples from 20 healthy blood donors, only 2 (10%) had Polyomavirus viruria, each 1 containing the BK and the JC viruses (5%). Compared with healthy blood donors, the percentage of patients with the JC virus viruria, but not the BK virus viruria was much higher in renal transplant recipients (χ2 = 7.623; P = .006). No Polyomavirus DNA was detected in plasma in those patients with viruria, and no Simian virus 40 DNA was found in any urine or plasma samples. Of 50 renal transplant recipients, 8 patients had cytomegalovirus infections after transplant, 7 of whom had simultaneous JC virus viruria.

Factor analyses
We attempted to analyze the reason for the higher rate of JC virus and the lower rate of BK virus infections in renal transplant recipients by comparing differences in renal transplant patients’ clinical characteristics, such as age, sex, immunosuppression therapy, acute rejection, cytomegalovirus infection, and hepatitis B virus and hepatitis C virus infections among the 3 groups containing BK virus-infected, JC virus-infected, and Polyomavirus-uninfected patients, as in some reports describing risk factors for Polyomavirus infection.15, 16 We observed no significant difference in age, sex, acute rejection, or hepatitis C virus infections among the 3 groups, but significant differences did exist in immuno­suppression therapy and cytomegalovirus and hepatitis B virus infections (χ2 = 11.332; P = .003; χ2 =7.951; P = .019; and χ2 =24.342; P = .000) (Table 1).

Patients infected with cytomegalovirus or using triple-drug immunosuppression, consisting of mycophenolate mofetil, prednisone, and cyclosporine were more susceptible to infection with the JC virus (χ2 = 6.023; P = .014; χ2 = 11.055; P = .001). Patients infected with hepatitis B virus pretransplant were more prone to infection with the BK virus (P = .028).

Renal function comparison
To investigate the influence of the BK virus or the JC virus infection on renal function in the early stages after surgery, we compared the glomerular filtration rate levels of patients in the 3 groups. The glomerular filtration rate of patients with the BK virus and the JC virus infections and patients without infections were 86.47 ± 29.990 mL/min•1.73 m2, 78.76 ± 14.377 mL/min•1.73 m2, and 82.71 ± 35.414 mL/min•1.73 m2. The differences between the 3 groups were not statistically significant (χ2 = 0.228; P = .892) (Table 1).

Discussion

Polyomavirus is one of the most common viruses for opportunistic infection in renal transplant recipients.5 Both urine cytology and molecular-based methods can be used in detecting Polyomavirus infection after renal transplant.17 Possession of a simple, rapid, sensitive feature, with capability to distinguish the BK virus, the JC virus, and the Simian virus 40, polymerase chain reaction technology is gradually being substituted for urine cytology with deficiencies for complex, poor specificity, vulnerable effect by urine components, and the inability to distinguish the type of Polyomavirus.17 Polymerase chain reaction technology is also increasingly considered as the criterion standard for detecting Polyomavirus infection.17 It was considered a reliable and advisable method of detecting Polyomavirus DNA in urine by nested polymerase chain reaction combined with Polyomavirus-specific sequence analysis in this study.

In this prospective study, we demonstrated a 46% Polyomavirus viruria rate, including a 4% BK virus and 42% JC virus viruria rate in renal transplant recipients, while it was only 10% in healthy blood donors, each with 5% BK virus and JC virus viruria. No recipient had Polyomavirus viremia, and Simian virus 40 was not found in any urine or plasma sample. No association between the BK virus or the JC virus viruria and renal dysfunction was observed.

The incidence of Polyomavirus viruria varies from 5% to 20% among healthy people and increases significantly in renal transplant recipients, varying between 10% and 60%.18 Usually, the incidence of BK virus viruria (which ranges from 23% to 57%) is much higher than that of the JC virus (approximately 22%)1, 12, 19 after surgery. However, our study demonstrated opposite results. A much higher rate of JC virus viruria (42%) than BK virus viruria (4%) was demonstrated, and this is consistent with the report of Priftakis and associates.18 After analyzing potential reasons for this15, 16—prednisone + mycophenolate mofetil + cyclosporine immuno­suppression therapy—cytomegalovirus infection, and hepatitis B virus infection were found to be the most-likely influencing factors. Further analysis revealed that cytomegalovirus infection and immuno­suppression by mycophenolate mofetil + prednisone + cyclosporine were more likely associated with JC virus infection. Hepatitis B virus infection pretransplant was more prone to affect BK virus infection.

Immunosuppressive drugs are usually regarded as one of the most-common risk factors for Polyomavirus infections15; their influence on Polyomavirus infections is remains controversial. Some studies20, 21 have reported that an immunosuppressive regimen containing tacrolimus, mycophenolate mofetil, or both could significantly increase the risk of BK virus infection, while another15 reported that triple combinations of prednisone + azathioprine + cyclosporine may be associated with BK virus infection. However, most studies have failed to find a correlation between the frequency of JC virus viruria and the use of immunosuppressive drugs.5, 22 Unlike the above studies, we found that JC virus as opposed to BK virus infections was associated with immuno­suppressive treatment. Patients infected with the JC virus were more likely to use prednisone + mycophenolate mofetil + cyclosporine. The level of immunosuppression and specific BK virus or JC virus subtype, as opposed to specific immunosuppressive drugs, were key risk factors for Polyomavirus infection.1, 15 The different degree of immunosuppression generated by different combinations of immunosuppressive drugs may be involved in this disparity.

Cytomegalovirus is involved in immunoregulation, by modulating molecules involved in immune recognition and inflammation.23 As a result, cytomegalovirus could lead to a higher risk of opportunistic infections by inducing a general nonspecific immunosuppressive syndrome.23 Interaction between cytomegalovirus and Polyomavirus infections have been reported.24 Here, we demonstrated that cytomegalovirus replication enhanced JC virus replication, consistent with other reports.25, 26 The mechanism of action may be as follows: cytomegalovirus infection and expression of the cytomegalovirus immediate—early 2 gene activate early promoters of JC virus (which induce expression of T-antigen), and various late JC virus genes are then replicated and expressed.26

In 2 renal transplant recipients, BK virus infection occurred after renal transplant, and they were infected with hepatitis B virus before transplant. Thus, it seems that BK virus infection may be more likely in those with hepatitis B virus infection pretransplant. This may be related to hepatitis B virus-selective transactivation of a specific type of Polyomavirus (BK virus). Further study of the relation and the mechanism is needed.

As genitourinary tract epithelium is the site of Polyomavirus latency,2 virions likely enter the circulation through peritubular capillaries, after tubular damage, and release free virus in the interstitial compartment11, 12; thus, it seems unlikely that renal transplant patients would have viremia in the absence of viruria.11 Also, nested Polyomavirus polymerase chain reaction of the blood samples in our study was performed only on 23 patients with viruria, which is unlikely to have missed any cases of viremia. The BK virus or the JC virus viremia usually occur approximately 100 days after transplant.24 Considering the 3-month posttransplant visits in our study, it is not surprising that we did not observe patients with viremia in these early stages. The association between BK virus or JC virus infection and posttransplant renal dysfunction is controversial. Here, we did not observe any differences in the glomerular filtration rate among the BK virus- and the JC virus-infected and uninfected patients, consistent with previous reports.11, 12, 27

Other reports6, 28 suggest the opposite. However, their study designs include patients from 1 day to more than 25 years posttransplant. Given that graft dysfunction usually occurs after viremia and Polyomavirus nephropathy in the eighth month after surgery,11 and considering Ramos’s theory of the 3 stages of Polyomavirus infection,29 it is not surprising that we did not find renal dysfunction in any Polyomavirus-infected patient. We followed our renal transplant recipients for only 3 months after surgery; Polyomavirus infection would still be in the second stage, in which there is no viremia, no clinical abnormality, and normal renal function.

In sum, Polyomavirus, especially the JC virus, infection is not uncommon in Chinese renal transplant recipients. The higher incidence of JC virus infection was likely due to cytomegalovirus infection and immunosuppression, induced by prednisone + mycophenolate mofetil + cyclosporine. Thus, clinicians should be alert to the potential for JC viral infection in renal transplant recipients, especially those possessing the above risk factors. However, we failed to observe any association between JC virus infection and renal function in the early stages. In recent years, there has been no lack of reports about JC virus-associated tubulointerstitial nephritis in the later stages of renal transplant.30

As international guidelines recommend, not only should we monitor for BK virus infection, but also for JC viral infection after renal transplant.31 Monitoring of the JC virus infection will provided a new vision for diagnosing BK virus-uncorrelated Polyomavirus nephropathy in renal transplant recipients. Early detection of the BK virus or JC virus infection will effectively decrease the incidence of Polyomavirus nephropathy via effective intervention, such as extenuation or adjustment of the immunosuppressive treatment regimen.8, 32


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Volume : 9
Issue : 3
Pages : 175 - 180


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From the State key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China.
Acknowledgements: This study was supported by the National Basic Research Program of China (2007CB513005), and the Science Research Foundation of Heath Department of China (WKJ2009-2-023), and the National Natural Science Foundation of China (30872239), and the Independent Research topics of State key Laboratory for Diagnosis and Treatment of Infectious Diseases.
Address reprint requests to: Weihang Ma, State key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China.
Phone: +86 571 87236581
Fax: +86 571 87236459
E-mail: maweihangzy@163.com