Polyomavirus Disease Under New Immunosuppressive Drugs

Binet, Isabelle; Nickeleit, Volker; Hirsch, Hans H.; Prince, Olivier D.; Dalquen, Peter; Gudat, F; Mihatsch, Michael J.; Thiel, G

doi:10.1097/00007890-199903270-00022

Cited by 409 publications

(89 citation statements)

References 9 publications

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“…In this study, the distribution values of viruria/viremia was also not related to immunosuppressive therapy although the combinaison [Tac + prednisolone + MMF] was more but not statistically significant prescribed in all groups. Moreover, several studies reported that persistent BKV replication in renal allograft recipients was identified as a cause of progressive graft dysfunction and graft loss linked to immunosuppressive drugs (Tac + MMF) [3,7,10]. These findings contrast with those of this study revealed that 3 cases of acute rejections occurred in 2 patients G3 and 1 transplant recipient G4 who received this drug combina-tion.…”

Section: Discussioncontrasting

confidence: 97%

“…BKV reactivation in urinary tractus, which is usually asymptomatic viruria, may occur in both immunocompetent subjects, and immunocompromised patients leading to polyomavirus associated nephropathy (PVAN) that has recently reported as a cause of allograft failure in renal transplant recipients. This nephropathy seems to be related to the conjunction of an intensive immunosuppressive regiments containing tacrolimus (Tac) or mycophenolate mofetil (MMF), an immuno-allogenic environment, a viral reactivation and a renal tubular damages caused by ischaemia or rejection [1][2][3][4]. As previously retrospective studies repported, this PVAN would be associated with loss of allograft function occurring in about half of the cases and with a major fibrosis in more than 75% of the cases in renal transplantation [5,6].…”

Section: Introductionmentioning

confidence: 99%

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The Monitoring Interest of BK Virus Load in Renal Allograft Tunisian Recipients: Prospective Study

Gorgi¹,

Bacha²,

Sfar³

et al. 2012

OJOTS

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BK virus (BKV) may cause nephropathy in renal transplant recipients receiving immunosuppressive therapy, resulting in renal dysfunction and, possibly graft loss. However, the positive and negative predictive values of BK viral load are still controversial. In this prospective, single-center study, BKV DNA was measured 1, 3 and 6 months after transplantation. The viral load in urine and plasma was quantified with the real-time Q-PCR (Argen kit) in 73 renal allograft recipients Three of them showed acute rejection. To determine the cutoff value of viral load, 60 sera samples of healthy blood donors, matched for age and sex, were tested. The mean plasmatic viral load one month posttransplantation was statistically higher in renal transplant recipients (17.23 copies/ml) compared to that in controls (2 copies/ml) (p: 0.06). This difference of the distribution of viremia values is more evident in the third and sixth month (p: 0.002 and 0.010 respectively). Furthermore, analysis of the kinetic of viral load revealed an average rise of viremia at 3 months (1589.14 copies/ml) followed by its decrease at 6 months (249.75 copies/ml). However, the difference was not statistically significant. The same is true for the distribution of values of viruria and in all cases the average viral load was statistically higher in urine than in plasma. In addition, this study did not shown significant relationsheep between viremia/viruria and the occurrence of acute rejection, the renal function deterioration, the source of allograft or immunosuppressive therapy protocol. If the results of this study demonstrate the importance of the replication of BKV in renal transplant patients from the first month compared to that in immunocompetent subjects, the screening of the DNA of this virus does not appear to have a prognostic value in the occurrence of acute rejection. However, the plasma and urine monitoring of BKV load beyond 6 months, not appear to exclude the relationsheep between these two biomarkers and the occurrence of chronic graft dysfunction.

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Section: Discussioncontrasting

confidence: 97%

Section: Introductionmentioning

confidence: 99%

The Monitoring Interest of BK Virus Load in Renal Allograft Tunisian Recipients: Prospective Study

Gorgi¹,

Bacha²,

Sfar³

et al. 2012

OJOTS

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“…BKPyV‐associated nephropathy has been sporadically reported prior to the cyclosporine‐A (CsA) era 26, 27, but most cases have emerged after widespread clinical use of tacrolimus (TAC) and TAC‐mycophenolate 28, 29, 30, 31, 32. Data from large registries of 35 000 and more KT patients report a significantly increased risk of BKPyV for TAC‐ compared to CsA‐based regimens, while a reduced risk of BKPyV was seen for mammalian target of rapamycin (mTOR) inhibitor‐containing therapies 21, 22.…”

Section: Introductionmentioning

confidence: 99%

BK Polyomavirus Replication in Renal Tubular Epithelial Cells Is Inhibited by Sirolimus, but Activated by Tacrolimus Through a Pathway Involving FKBP-12

Hirsch

Yakhontova

et al. 2016

American Journal of Transplantation

108

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BK polyomavirus (BKPyV) replication causes nephropathy and premature kidney transplant failure. Insufficient BKPyV‐specific T cell control is regarded as a key mechanism, but direct effects of immunosuppressive drugs on BKPyV replication might play an additional role. We compared the effects of mammalian target of rapamycin (mTOR)‐ and calcineurin‐inhibitors on BKPyV replication in primary human renal tubular epithelial cells. Sirolimus impaired BKPyV replication with a 90% inhibitory concentration of 4 ng/mL by interfering with mTOR–SP6‐kinase activation. Sirolimus inhibition was rapid and effective up to 24 h postinfection during viral early gene expression, but not thereafter, during viral late gene expression. The mTORC‐1 kinase inhibitor torin‐1 showed a similar inhibition profile, supporting the notion that early steps of BKPyV replication depend on mTOR activity. Cyclosporine A also inhibited BKPyV replication, while tacrolimus activated BKPyV replication and reversed sirolimus inhibition. FK binding protein 12kda (FKBP‐12) siRNA knockdown abrogated sirolimus inhibition and increased BKPyV replication similar to adding tacrolimus. Thus, sirolimus and tacrolimus exert opposite effects on BKPyV replication in renal tubular epithelial cells by a mechanism involving FKBP‐12 as common target. Immunosuppressive drugs may therefore contribute directly to the risk of BKPyV replication and nephropathy besides suppressing T cell functions. The data provide rationales for clinical trials aiming at reducing the risk of BKPyV replication and disease in kidney transplantation.

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“…Consequently, polyomavirus‐associated nephropathy (PyVAN) occurs in 1–15% of kidney transplant recipients (KTRs), whereas polyomavirus‐associated hemorrhagic cystitis (PyVHC) affects 5–20% of allogeneic hematopoietic stem cell transplant patients 2, 9, 10. PyVAN and PyVHC have a significant impact on morbidity and graft and patient survival 11, 12, 13, 14, 15, 16, 17, 18. Despite considerable virologic research 19, 20, 21, 22, 23, randomized clinical studies either are lacking or failed to demonstrate effective antiviral therapies 24.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Immunodominant BK Polyomavirus 9mer Epitope T Cell Responses

Cioni

Leboeuf

Comoli

et al. 2016

American Journal of Transplantation

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Uncontrolled BK polyomavirus (BKPyV) replication in kidney transplant recipients (KTRs) causes polyomavirus‐associated nephropathy and allograft loss. Reducing immunosuppression is associated with clearing viremia and nephropathy and increasing BKPyV‐specific T cell responses in most patients; however, current immunoassays have limited sensitivity, target mostly CD4+ T cells, and largely fail to predict onset and clearance of BKPyV replication. To characterize BKPyV‐specific CD8+ T cells, bioinformatics were used to predict 9mer epitopes in the early viral gene region (EVGR) presented by 14 common HLAs in Europe and North America. Thirty‐nine EVGR epitopes were experimentally confirmed by interferon‐γ enzyme‐linked immunospot assays in at least 30% of BKPyV IgG–seropositive healthy participants. Most 9mers clustered in domains, and some were presented by more than one HLA class I, as typically seen for immunodominant epitopes. Specific T cell binding using MHC class I streptamers was demonstrated for 21 of 39 (54%) epitopes. In a prospective cohort of 118 pediatric KTRs, 19 patients protected or recovering from BKPyV viremia were experimentally tested, and 13 epitopes were validated. Single HLA mismatches were not associated with viremia, suggesting that failing immune control likely involves multiple factors including maintenance immunosuppression. Combining BKPyV load and T cell assays using immunodominant epitopes may help in evaluating risk and reducing immunosuppression and may lead to safe adoptive T cell transfer.

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Polyomavirus Disease Under New Immunosuppressive Drugs

Abstract: Recurrent rejection episodes and high dose immunosuppressive therapy, including tacrolimus, are risk factors for manifest PV kidney graft infection, which has an ominous prognosis.

Cited by 409 publications

References 9 publications

The Monitoring Interest of BK Virus Load in Renal Allograft Tunisian Recipients: Prospective Study

The Monitoring Interest of BK Virus Load in Renal Allograft Tunisian Recipients: Prospective Study

BK Polyomavirus Replication in Renal Tubular Epithelial Cells Is Inhibited by Sirolimus, but Activated by Tacrolimus Through a Pathway Involving FKBP-12

Characterization of Immunodominant BK Polyomavirus 9mer Epitope T Cell Responses

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