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Polyomavirus-associated nephropathy (PyVAN) and hemorrhagic cystitis (PyVHC) occur almost exclusively after kidney transplantation (KT) and allogeneic hematopoietic stem cell transplantation (HSCT), respectively. In addition, PyV-associated urothelial cancer (PyVUC) is emerging after KT. These diseases are attributed to BK polyomavirus (BKPyV), a small non-enveloped, doublestranded DNA virus infecting >90% of the general population followed by renal persistence. PyVAN causes premature allograft failure in 1–15% of KT, while PyVHC complicates 5–25% of allogeneic HSCT with excess morbidity. PyVUC is currently diagnosed in <1% of KT but impacts graft and patient survival. Insufficient antiviral immunity post-transplant is key to extensive replicative cytopathic damage seen in PyVAN and PyVHC by epithelial denudation, inflammation, and fibrotic scarring while permitting genetic accidents including chromosomally integrated viral genomes in PyVUC. However, immunosuppression alone is not sufficient since heart and lung transplant recipients are rarely affected despite more intense immunosuppression. Specific cofactors have been postulated in addition to the allogeneic constellation between the BKPyVreplicating host cell and the respective immune effectors. In KT, a mismatch between a high renal BKPyV load in the transplant and a low number of recipient immune effector functions is proposed in addition to tacrolimus, mycophenolate, and steroids. In allogeneic HSCT, bladder-toxic conditioning, e.g., by cyclophosphamide, is proposed to cause subclinical rarefication of the bladder urothelium, which becomes clinically overt by high-level BKPyV replication and inflammatory exacerbation post-engraftment. Long-standing failure to resume immune control may allow for genetic replicative accidents and outgrowth of PyVUC. In PyVAN and PyVHC, high-level viruria and plasma BKPyV-DNAemia correlate with disease activity and could assist in developing antiviral drugs currently lacking. Early stepwise reduction of immunosuppression is recommended in KT, an option severely limited in PyVHC by imminent graft-versus-host disease. Phase I/II study results are awaited investigating mTOR (mechanistic target of rapamycin) inhibitors, low-dose cyclosporine, leflunomide, intravenous immunoglobulin, monoclonal antibodies, and T-cell therapy. Until then, PyVAN, PyVHC, and PyVUC will continue to represent significant unmet clinical needs in transplant medicine jeopardizing otherwise successful outcomes.

DOI: 10.1007/978-3-030-01751-4_29-1