Background

Polyomavirus-associated nephropathy (PVAN) is an emerging cause of kidney transplant failure affecting 1-10% of patients. As uncertainty exists regarding risk factors, diagnosis, and intervention, an independent panel of experts reviewed the currently available evidence and prepared this report. Most cases of PVAN are elicited by BK virus (BKV) in the context of intense immunosuppression. No specific immunosuppressive drug is exclusively associated with PVAN, but most cases reported to date arise while the patient is on triple immunosuppressive combinations, often comprising tacrolimus and/or mycophenolate mofetil plus corticosteroids. Immunologic control of polyomavirus replication can be achieved by reducing, switching, and/or discontinuing components of the immunosuppressive regimen, but the individual's risk of rejection should be considered. The success rate of this intervention is increased with earlier diagnosis. Therefore, it is recommended that all renal transplant recipients should be screened for BKV replication in the urine: 1) every three months during the first two years posttransplant; 2) when allograft dysfunction is noted; and 3) when allograft biopsy is performed. A positive screening result should be confirmed in <4 weeks and assessed by quantitative assays (e.g. BKV DNA or RNA load in plasma or urine). Definitive diagnosis of PVAN requires allograft biopsy. If PVAN and concurrent acute rejection is diagnosed, antirejection treatment should be considered, coupled with subsequently reducing immunosuppression. The antiviral cidofovir is not approved for PVAN, but investigational use at low doses (0.25-0.33 mg/kg intravenously biweekly) without probenicid should be considered for refractory cases. Retransplantation after renal allograft loss to PVAN remains a treatment option for patients clearing polyomavirus replication.

Polyomavirus hominis 1, better known as BK virus (BKV), infects up to 90% of the general population. However, significant clinical manifestations are rare and limited to individuals with impaired immune functions. BKV has been associated with diverse entities such as haemorrhagic cystitis, ureteric stenosis, vasculopathy, pneumonitis, encephalitis, retinitis, and even multi-organ failure. In addition, BKV has been implicated in autoimmune disease and possibly cancer. Due to high prevalence and frequent reactivation, the role of BKV in some of these pathologies has been difficult to define. Development of BKV diseases is likely to require complementing determinants in the host, the target organ, and possibly the virus, that are subject to modulators such as immunosuppression. These complex aspects are highlighted in polyomavirus-associated nephropathy (PAN), an emerging disease in renal allograft recipients that may jeopardise the progress in renal transplantation accomplished in the past 10 years. Intervention is difficult due to the lack of specific antivirals and relies mostly on improving immune control. Diagnostic strategies using urine cytology and BKV load measurements in plasma have led to earlier diagnosis of PAN, which increased the success rate of intervention. Case series suggest that cidofovir might be effective, especially when combined with reduced immunosuppression.

Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality in transplant recipients. For the purpose of developing consistent reporting of CMV outcomes in clinical trials, definitions of CMV infection and disease were developed and most recently published in 2002. Since then, there have been major developments in its diagnosis and management. Therefore, the CMV Drug Development Forum consisting of scientists, clinicians, regulators, and industry representatives has produced an updated version incorporating recent knowledge with the aim to support clinical research and drug development. The main changes compared to previous definitions are the introduction of a "probable disease" category and to incorporate quantitative nucleic acid testing in some end-organ disease categories. As the field evolves, the need for updates of these definitions is clear, and collaborative efforts between scientists, regulators, and industry can provide a platform for this work.

Our study provides important data about polyomavirus infection and replication in healthy, immunocompetent individuals. These data indicate significant differences between BKV and JCV with respect to virus-host interaction and epidemiology.

The human BK polyomavirus (BKV) is the major cause of polyomavirus-associated nephropathy (Py-VAN) putting 1-15% of kidney transplant patients at risk of premature allograft failure, but is less common in other solid organ transplants. Because effective antiviral therapies are lacking, screening kidney transplant patients for BKV replication in urine and blood has become the key recommendation to guide the reduction of immunosuppression in patients with BKV viremia. This intervention allows for expanding BKV-specific cellular immune responses, curtailing of BKV replication in the graft, and clearance of BKV viremia in 70-90% patients. Postintervention rejection episodes occur in 8-12%, most of which are corticosteroid responsive. Late diagnosis is faced with irreversible functional decline, poor treatment response, and graft loss. Adjunct therapies such as cidofovir, leflunomide and intravenous immunoglobulins have been used, but the benefit is not documented in trials. Retransplantation after PyVAN is largely successful, but requires close monitoring for recurrent BKV viremia.

Polyomavirus-associated nephropathy (PVAN) is

Testing for BK virus DNA in plasma from renal-allograft recipients with use of the polymerase chain reaction is a sensitive and specific method for identifying viral nephropathy.