Acute kidney injury (AKI) in paediatric kidney transplant recipients is common. Infection including urinary tract infection (UTI) and rejection are the most common causes in children. Surgical complications often cause AKI early post-transplant, whereas BK polyomavirus nephropathy rarely occurs in the first month post-transplant. Understanding kidney physiology helps to appreciate the sensitivity of the allograft to AKI, more so than native kidneys. Although the cause of AKI is often multi-factorial, there may be an underlying process that is treatable. Eliciting the aetiology, in this regard, is of paramount importance. Pre-renal and post-renal causes of allograft dysfunction are important to distinguish from intrinsic kidney disease. Clinical information and examination of fluid balance, urine dipstick testing, blood tests, bladder and kidney transplant ultrasound, and kidney transplant biopsy remain vital assessment tools in narrowing the differential diagnosis. A careful prescribed and recreational drug history is always warranted as many drugs including supplements are nephrotoxic. Additional causes such as allograft rejection, recurrent disease, and calcineurin inhibitor toxicity need to be considered in cases of allograft dysfunction, which would not affect the native kidneys. Early detection and assessment of AKI is crucial in promoting recovery. Significant progress has been made in specific pathologies over the last 20 years, which has improved kidney allograft survival rates considerably. Research into identifying AKI biomarkers to assist early diagnosis, before the serum creatinine rises, is ongoing.

BK polyomavirus-associated nephropathy (BKPyVAN) is an important cause of allograft dysfunction and failure in kidney transplant recipients (KTRs) and there are no proven effective treatments. Case reports and in vitro data support the potential activity of cidofovir against BK polyomavirus (BKPyV).

We report the results of a phase I/II, double-blind, placebo-controlled randomized dose-escalation trial of cidofovir in KTRs with biopsy-confirmed BKPyVAN and estimated glomerular filtration rate ≥30 mL/min. Intravenous cidofovir (0.25 mg/kg/dose or 0.5 mg/kg/dose) or placebo was administered on days 0, 7, 21, and 35, with final follow-up through day 49.

The trial was prematurely discontinued due to slow accrual after 22 KTRs had completed the study. Cidofovir was safe and tolerated at the doses and duration studied. The proportion of subjects with any adverse event (AE) was similar between groups (9/14 [64%] in the combined cidofovir dose groups and 6/8 [75%] in the placebo group); 84% of AEs were mild. BKPyV DNAemia reduction by day 49 was similar between groups (>1 log10 reduction in (2/9 [22.2%] of 0.25 mg/kg group, 1/5 [20%] of 0.5 mg/kg group, and 2/8 [25%] of placebo group).

These preliminary results indicate that low-dose cidofovir was safe and tolerated but had no significant BKPyV-specific antiviral effect in KTRs with BKPyVAN.

BK polyomavirus (BKPyV) remains a significant challenge after kidney transplantation. International experts reviewed current evidence and updated recommendations according to Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Risk factors for BKPyV-DNAemia and biopsy-proven BKPyV-nephropathy include recipient older age, male sex, donor BKPyV-viruria, BKPyV-seropositive donor/-seronegative recipient, tacrolimus, acute rejection, and higher steroid exposure. To facilitate early intervention with limited allograft damage, all kidney transplant recipients should be screened monthly for plasma BKPyV-DNAemia loads until month 9, then every 3 mo until 2 y posttransplant (3 y for children). In resource-limited settings, urine cytology screening at similar time points can exclude BKPyV-nephropathy, and testing for plasma BKPyV-DNAemia when decoy cells are detectable. For patients with BKPyV-DNAemia loads persisting >1000 copies/mL, or exceeding 10 000 copies/mL (or equivalent), or with biopsy-proven BKPyV-nephropathy, immunosuppression should be reduced according to predefined steps targeting antiproliferative drugs, calcineurin inhibitors, or both. In adults without graft dysfunction, kidney allograft biopsy is not required unless the immunological risk is high. For children with persisting BKPyV-DNAemia, allograft biopsy may be considered even without graft dysfunction. Allograft biopsies should be interpreted in the context of all clinical and laboratory findings, including plasma BKPyV-DNAemia. Immunohistochemistry is preferred for diagnosing biopsy-proven BKPyV-nephropathy. Routine screening using the proposed strategies is cost-effective, improves clinical outcomes and quality of life. Kidney retransplantation subsequent to BKPyV-nephropathy is feasible in otherwise eligible recipients if BKPyV-DNAemia is undetectable; routine graft nephrectomy is not recommended. Current studies do not support the usage of leflunomide, cidofovir, quinolones, or IVIGs. Patients considered for experimental treatments (antivirals, vaccines, neutralizing antibodies, and adoptive T cells) should be enrolled in clinical trials.

Viral infections have been considered as a major cause of morbidity and mortality after kidney transplantation in pediatric cohort. Children are at high risk of acquiring virus-related complications due to immunological immaturity and the enhanced alloreactivity risk that led to maintenance of high immunosuppressive regimes. Hence, prevention, early detection, and prompt treatment of such infe ctions are of paramount importance. Among all viral infections, herpes viruses (herpes simplex virus, varicella zoster virus, Epstein-Barr virus, cytomegalovirus), hepatitis B and C viruses, BK polyomavirus, and respiratory viruses (respiratory syncytial virus, parainfluenza virus, influenza virus and adenovirus) are common in kidney transplant recipients. These viruses can cause systemic disease or allograft dysfunction affecting the clinical outcome. Recent advances in tech nology and antiviral therapy have improved management strategies in screening, monitoring, adoption of prophylactic or preemptive therapy and precise trea tment in the immunocompromised host, with significant impact on the outcome. This review discusses the etiology, screening and monitoring, diagnosis, pre vention, and treatment of common viral infections in pediatric renal transplant recipients.

Metagenomics revealed novel and routinely overlooked viruses, representing sources of unrecognized infections after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aim to describe DNA and RNA virus prevalence and kinetics in allo-HSCT recipients' plasma for one year post HSCT. We included 109 adult patients with first allo-HSCT from 1 March 2017 to 31 January 2019 in this observational cohort study. Seventeen DNA and three RNA viral species were screened with qualitative and/or quantitative r(RT)-PCR assays using plasma samples collected at 0, 1, 3, 6, and 12 months post HSCT. TTV infected 97% of patients, followed by HPgV-1 (prevalence: 26-36%). TTV (median 3.29 × 10⁵ copies/mL) and HPgV-1 (median 1.18 × 10⁶ copies/mL) viral loads peaked at month 3. At least one Polyomaviridae virus (BKPyV, JCPyV, MCPyV, HPyV6/7) was detected in >10% of patients. HPyV6 and HPyV7 prevalence reached 27% and 12% at month 3; CMV prevalence reached 27%. HSV, VZV, EBV, HHV-7, HAdV and B19V prevalence remained <5%. HPyV9, TSPyV, HBoV, EV and HPg-V2 were never detected. At month 3, 72% of patients had co-infections. TTV and HPgV-1 infections were highly prevalent. BKPyV, MCPyV and HPyV6/7 were frequently detected relative to classical culprits. Further investigation is needed into associations between these viral infections and immune reconstitution or clinical outcomes.

In 2019, there were about 100,000 kidney transplants globally, with more than a quarter of them performed in the United States. Unfortunately, some engrafted organs are lost to polyomavirus-associated nephropathy (PyVAN) caused by BK and JC viruses (BKPyV and JCPyV). Both viruses cause brain disease and possibly bladder cancer in immunosuppressed individuals. Transplant patients are routinely monitored for BKPyV viremia, which is an accepted hallmark of nascent nephropathy. If viremia is detected, a reduction in immunosuppressive therapy is standard care, but the intervention comes with increased risk of immune rejection of the engrafted organ. Recent reports have suggested that transplant recipients with high levels of polyomavirus-neutralizing antibodies are protected against PyVAN. Virus-like particle (VLP) vaccines, similar to approved human papillomavirus vaccines, have an excellent safety record and are known to induce high levels of neutralizing antibodies and long-lasting protection from infection. In this study, we demonstrate that VLPs representing BKPyV genotypes I, II, and IV, as well as JCPyV genotype 2 produced in insect cells elicit robust antibody titers. In rhesus macaques, all monkeys developed neutralizing antibody titers above a previously proposed protective threshold of 10,000. A second inoculation, administered 19 weeks after priming, boosted titers to a plateau of ≥ 25,000 that was maintained for almost two years. No vaccine-related adverse events were observed in any macaques. A multivalent BK/JC VLP immunogen did not show inferiority compared to the single-genotype VLP immunogens. Considering these encouraging results, we believe a clinical trial administering the multivalent VLP vaccine in patients waiting to receive a kidney transplant is warranted to evaluate its ability to reduce or eliminate PyVAN.

BK polyomavirus has been well-studied as an opportunistic infection in immunocompromised kidney transplant patients. In the majority of the population, BK polyomavirus establishes a lifelong infection in renal tubular and uroepithelial cells; however, in an immunocompromised state, the virus can reactivate and can lead to BK polyomavirus-associated nephropathy (BKN). In this case, the patient was a 46-year-old male with a past medical history of HIV, compliant with antiretroviral therapy (ART), and B-cell lymphoma treated with chemotherapy. The patient presented with worsening kidney function of unknown etiology. This prompted further assessment with a kidney biopsy. Kidney biopsy findings were consistent with BKN. In the literature, BKN has been studied in renal transplant patients; however, it rarely involves native kidneys.

BK virus maintains a latent infection that is ubiquitous in humans. It has a propensity for reactivation in the setting of a dysfunctional cellular immune response and is frequently encountered in kidney transplant recipients. Screening for the virus has been effective in preventing progression to nephropathy and graft loss. However, it can be a diagnostic and therapeutic challenge. In this in-depth state-of-the-art review, we will discuss the history of the virus, virology, epidemiology, cellular response, pathogenesis, methods of screening and diagnosis, evidence-based treatment strategies, and upcoming therapeutics, along with the issue of re-transplantation in patients.

The aims were to investigate the incidence of BKV infection and the presence of HC in pediatric patients undergoing HSCT. Twenty-four children patients (M/F: 17/7) undergoing HSCT in a single center over a period of 1 year were included in the study. The presence of BKV DNA was determined by quantitative real-time PCR in plasma and urine samples at the following times: before transplantation, twice a week until engraftment time, and weekly for + 100 days. The mean age of the patients was 7.79 ± 5.03 years, the mean follow-up time was 95.6 ± 25.9 days, and the average number of samples per patient was 15.8 ± 3.2. BKV DNA was detected in at least one urine sample in 91.6% (n: 22) and at least one plasma sample in 75% (n:18) of the patients. The median time to the first BKV DNA positivity in urine and plasma samples was 11 (range: 1-80) and 32 days (range: 2-79), respectively. The median value of BKV DNA copies in urine and plasma were 1.7 × 10⁶ (range: 2.8 × 10¹ -1.2 × 10¹⁴ ) and 1.9 × 10³ copies/mL (range: 3-2.1 × 10⁶ ), respectively. Thirteen patients (54.2%) had hematuria with BKV viruria; 8 (33.3%) patients had viremia. The median value of the BKV DNA copies in urine and plasma was 4.4 × 10⁷ (range: 65-1 × 10¹¹ ) and 2.9 × 10³ (range: 7-7.8 × 10⁴ ) copies/mL in these patients. Two (15.4%) of the 13 patients with BKV viruria and hematuria were diagnosed with BKV-related HC. BKV DNA viral load monitoring of urine and plasma in pediatric HSCT patients with a high risk for viral infections is valuable for understanding the development of BKV-related HC.

Polyomavirus infections occur commonly in humans and are normally nonfatal. However, in immunocompromised individuals, they are intractable and frequently fatal. Due to a lack of approved drugs to treat polyomavirus infections, cidofovir, a phosphonate nucleotide analog approved to treat cytomegalovirus infections, has been repurposed as an antipolyomavirus agent. Cidofovir has been modified in various ways to improve its efficacies as a broad-spectrum antiviral agent. However, the actual mechanisms and targets of cidofovir and its modified derivatives as antipolyomavirus agents are still under research. Here, polyomavirus large tumor antigen (Tag) activities were identified as the viral target of cidofovir derivatives. The alkoxyalkyl ester derivatives of cidofovir efficiently inhibit polyomavirus DNA replication in cell-free human extracts and a viral in vitro replication system utilizing only purified proteins. We present evidence that DNA helicase and DNA binding activities of polyomavirus Tags are diminished in the presence of low concentrations of alkoxyalkyl ester derivatives of cidofovir, suggesting that the inhibition of viral DNA replication is at least in part mediated by inhibiting single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) binding activities of Tags. These findings show that the alkoxyalkyl ester derivatives of cidofovir are effective in vitro without undergoing further conversions, and we conclude that the inhibitory mechanisms of nucleotide analog-based drugs are more complex than previously believed.

BK virus nephropathy (BKN) is uncommonly reported in native kidneys; mostly reported in bone marrow transplant patients. This case report represents an interesting clinical scenario of biopsy-proven BKN in native kidneys, in the presence of more than one million copies/mL of BK virus in serum.

BK virus (BKV) is an opportunistic pathogen which causes significant morbidity and mortality in individuals who are immunodeficient. We aimed to quantitate and characterise BKV and to correlate with the degree of immunosuppression among human immunodeficiency virus (HIV)-1-infected individuals.

BKV DNA detection was carried out using an in-house quantitative real-time polymerase chain reaction on paired whole-blood and urine samples collected from 187 antiretroviral therapy (ART)-naïve HIV-1-infected individuals and 93 healthy individuals who served as controls. Sequencing was performed for a proportion of high BK viral load (VL) samples to observe non-coding control region (NCCR) rearrangements.

BKV positivity in urine was 25.6% among HIV-infected individuals and 10.7% in control individuals (P = 0.03). The BK VL showed a significant negative correlation with CD4+ T-cell counts, a positive correlation with WHO clinical staging and no significant correlation with HIV-1 VL. Of 42 BKVs from urine samples sequenced, two showed rearrangements without clinically severe disease or high VL. Their NCCR and VP1 sequence-based genotyping revealed genotype I. In a small subset of individuals (n = 8) on ART who were being followed up, six individuals showed either decrease or complete clearance of virus with ART.

There was a higher frequency of BK viruria in HIV-1-infected individuals than among healthy controls and the positivity correlated with the degree of immunosuppression. There was no association of high VL with NCCR rearrangements in urine.

The objective of this review was to summarize the recent literature describing the current burden of disease due to herpesviruses in the antiviral and transplant era; describe mechanisms of action of antiviral agents and the development of resistance; summarize the literature of recent antiviral agents brought to market as well as agents under development; and to present literature on future strategies for herpesvirus therapeutics.

An extensive search of the medical literature related to antiherpesviral therapy was conducted to compose this narrative review. Literature searches were performed via PubMed and ultimately 137 articles were included as most relevant to the scope of this article.

Herpesviruses are a family of DNA viruses that are ubiquitous throughout human populations and share the feature of establishing lifelong infections in a latent phase with the potential of periodic reactivation. With the exception of herpes simplex virus, varicella zoster virus, and Epstein-Barr virus, which have a significant disease burden in individuals with normal immune function, the morbidity and mortality of the remaining viruses are primarily associated with the immunocompromised host. Over the last half-century, several agents have been tested in large randomized, placebo-controlled trials that have resulted in safe and effective antiviral agents for the treatment of many of these infections.

With increasing use of antiherpesviral agents for extended periods, particularly in immunocompromised hosts, the emergence of resistant viruses has necessitated the development of newer agents with novel targets and better side-effect profiles.

This article focuses on the clinically relevant approved antiviral medications available for the treatment of infants and children. A brief overview of drug categories, mechanism of action, resistance, pharmacokinetics, and side effects is provided for the more commonly prescribed antivirals. The patient categories addressed are treatment and prophylaxis of influenza, neonatal herpes simplex virus and congenital cytomegalovirus, treatment and prophylaxis of viral disease in the immunocompromised host, and a brief introduction to the antivirals available to treat hepatitis B and hepatitis C in children.

Over the last 10 years, the number of identified polyomaviruses has grown to more than 35 subtypes, including 13 in humans. The polyomaviruses have similar genetic makeup, including genes that encode viral capsid proteins VP1, 2, and 3 and large and small T region proteins. The T proteins play a role in viral replication and have been implicated in viral chromosomal integration and possible dysregulation of growth factor genes. In humans, the Merkel cell polyomavirus has been shown to be highly associated with integration and the development of Merkel cell cancers. The first two human polyomaviruses discovered, BKPyV and JCPyV, are the causative agents for transplant-related kidney disease, BK commonly and JC rarely. JC has also been strongly associated with the development of progressive multifocal leukoencephalopathy (PML), a rare but serious infection in untreated HIV-1-infected individuals and in other immunosuppressed patients including those treated with monoclonal antibody therapies for autoimmune diseases systemic lupus erythematosus, rheumatoid arthritis, or multiple sclerosis. The trichodysplasia spinulosa-associated polyomavirus (TSAPyV) may be the causative agent of the rare skin disease trichodysplasia spinulosa. The remaining nine polyomaviruses have not been strongly associated with clinical disease to date. Antiviral therapies for these infections are under development. Antibodies specific for each of the 13 human polyomaviruses have been identified in a high percentage of normal individuals, indicating a high rate of exposure to each of the polyomaviruses in the human population. PCR methods are now available for detection of these viruses in a variety of clinical samples.

Polyomavirus nephropathy (PVN) is a major complication of kidney transplantation. Most reports describe polyomavirus viremia either precedes or is detectable at the time of diagnosis of PVN. This association is the basis of current screening recommendations. We retrospectively reviewed the PCR results of blood and urine samples from 29 kidney transplant recipients with biopsy-proven PVN. Biopsies were performed for a rise in serum creatinine or persistent high-level BK viruria. All biopsies showed polyoma virus large T-antigen expression in tubular epithelium using immunohistochemistry. All had viruria preceding or at the time of biopsy (range, 5.2 × 10⁴ to >25 × 10⁶ BKV DNA copies/ml). Twenty (69%) had viremia ranging from 2.5 × 10³ to 4.3 × 10⁶ copies/ml at the time of the biopsy. Via blood BK PCR assay, nine (31%) had no BK viremia detected either preceding or at the time of the biopsy. In five recipients where sufficient specimen permitted, additional plasma BK assessment revealed positive detection of viremia. A comparative analysis of assays from two centres was performed with spiked samples. BK DNA may not be detected in the blood of some kidney transplant recipients with histologically confirmed PVN. This may reflect limitation of whole blood as opposed to plasma-based BK DNA assessment.

BK virus belongs to Polyomaviridae family; it causes 95% of nephropathy cases related to polyomavirus, with the other 5% caused by JC virus. Nephropathy jeopardizes graft function, causing a premature failure of the graft in 1%-10% of patients with kidney transplants. Nowadays, antiviral effective treatment is unknown, which is why blood and urine screening of renal transplantation patients has become the most important recommendation to guide the decrease of immunosuppression, and the only proven method to decrease poor outcomes. Different interventions, such as cidofovir, leflunomide, fluoroquinolones, and intravenous immunoglobulin, have been attempted with no improvement at all. This review aims to summarize the most relevant features of BK virus, historical issues, transmission mechanisms, risk factors, and therapeutic interventions.

BK virus-hemorrhagic cystitis (BKV-HC) is a potential cause of morbidity and mortality in patients having undergone allogeneic stem cell transplantation (Allo-SCT). We analyzed the clinical features of BKV-HC following Allo-SCT and reported the utility of leflunomide therapy for BKV-HC.

From January 2005 to June 2014, among the 69 patients underwent Allo-SCT in our institution, the patients who experienced BKV-HC were investigated retrospectively.

Hemorrhagic cystitis (HC) was observed in 30 patients (43.5%), and among them, 18 patients (26.1%) were identified as BKV-HC. The median age of the patients (12 males and 6 females) was 45 years (range, 13-63). Patients received Allo-SCT from acute myeloid leukemia (n=11), aplastic anemia (n=4), myelodysplastic syndrome (n=2), and non-Hodgkin lymphoma (n=1).The donor types were a HLA-matched sibling donor for 6 patients, HLA-matched unrelated donor for 9, and a haploidentical familial donor for 2. The median onset and duration of BKV-HC was on day 21 (range, 7-97) after transplantation and 22 days (range, 6-107). Eleven patients (62.1%) had grade I-II HC and seven patients (38.9%) had grade III-IV (high-grade) HC. Among the seven patients who had high-grade HC, one had complete response (CR), one partial response (PR), and five no response (NR). Among the five non-responders, one died of BKV-HC associated complications. The remaining four patients were treated with leflunomide, with achieving CR (n=2) and PR (n=2). The median duration from the start of leflunomide therapy to response was 13 days (range, 8-17 days). All patients tolerated the leflunomide treatment well, with three patients having mild gastrointestinal symptoms, including anorexia and abdominal bloating.

BKV-HC was commonly observed in patients with HC following Allo-SCT. In high-grade BKV-HC patients who fail supportive care, leflunomide may be a feasible option without significant toxicity.

Human polyomaviruses (HPyVs) are a growing challenge in immunocompromised patients in view of the increasing number of now 12 HPyV species and their diverse disease potential. Currently, histological evidence of disease is available for BKPyV causing nephropathy and haemorrhagic cystitis, JCPyV causing progressive multifocal leukoencephalopathy and occasionally nephropathy, MCPyV causing Merkel cell carcinoma and TSPyV causing trichodysplasia spinulosa, the last two being proliferative skin diseases. Here, the current role of HPyV in solid organ transplantation (SOT) was reviewed and recommendations regarding screening, monitoring and intervention were made. Pre-transplant screening of SOT donor or recipient for serostatus or active replication is currently not recommended for any HPyV. Post-transplant, however, regular clinical search for skin lesions, including those associated with MCPyV or TSPyV, is recommended in all SOT recipients. Also, regular screening for BKPyV replication (e.g. by plasma viral load) is recommended in kidney transplant recipients. For SOT patients with probable or proven HPyV disease, reducing immunosuppression should be considered to permit regaining of immune control. Antivirals would be desirable for treating proven HPyV disease, but are solely considered as adjunct local treatment of trichodysplasia spinulosa, whereas surgical resection and chemotherapy are key in Merkel cell carcinoma. Overall, the quality of the clinical evidence and the strength of most recommendations are presently limited, but are expected to improve in the coming years.

Polyomavirus nephropathy is commonly seen in the renal allograft setting but is uncommon in native kidneys. This paper describes polyomavirus nephropathy that developed in the native kidneys of a patient following immunosuppressive therapy for rheumatoid arthritis/Sjögren's syndrome associated lung disease. The patient presented with dyspnoea and a slow steady rise in serum creatinine. Owing to chronic immunosuppression, calcineurin-inhibitor toxicity was suspected. However, renal biopsy revealed polyomavirus nephropathy. The treatment of choice, lowered immunosuppression, was complicated by exacerbation of the patient's lung disease. This case highlights features of polyomavirus nephropathy in the native kidney, as well as the difficulty in its treatment when immunosuppressive treatment is necessary for medical comorbidities.

Opportunistic viral infections are one of the major causes of morbidity and mortality in HIV infection and their molecular detection in the whole blood could be a useful diagnostic tool.

The frequency of opportunistic DNA virus infections among HIV-1-infected individuals using multiplex real-time PCR assays was studied.

The subjects were in two groups; group 1: Having CD4 counts<100 cells/µl (n=118) and the group 2: counts>350 cells/µl (n=173). Individuals were classified by WHO clinical staging system. Samples from 70 healthy individuals were tested as controls. In-house qualitative multiplex real-time PCR was standardised and whole blood samples from 291 were tested, followed by quantitative real-time PCR for positives. In a proportion of samples genotypes of Epstein-Barr virus (EBV) and CMV were determined.

The two major viral infections observed were EBV and CMV. The univariate analysis of CMV load showed significant association with cryptococcal meningitis, oral hairy leukoplakia (OHL), CMV retinitis, CD4 counts and WHO staging (P<0.05) while the multivariate analysis showed an association with OHL (P=0.02) and WHO staging (P=0.05). Univariate analysis showed an association of EBV load with CD4 counts and WHO staging (P<0.05) and multivariate analysis had association only with CD4 counts. The CMV load was significantly associated with elevated SGPT and SGOT level (P<0.05) while the EBV had only with SGOT.

This study showed an association of EBV and CMV load with CD4+ T cell counts, WHO staging and elevated liver enzymes. These viral infections can accelerate HIV disease and multiplex real-time PCR can be used for the early detection. Genotype 1 and 2 of EBV and genotype gB1 and gB2 of CMV were the prevalent in the HIV-1 subtype C-infected south Indians.

The acyclic nucleoside phosphonates [HPMPC: cidofovir, Vistide; PMEA: adefovir dipivoxil, Hepsera; and PMPA: tenofovir, Viread] have proven to be effective in vitro (cell culture systems) and in vivo (animal models and clinical studies) against a wide variety of DNA virus and retrovirus infections, for example, cidofovir against herpesvirus [herpes simplex virus type 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus type 6, 7 and 8), polyoma-, papilloma-, adeno- and poxvirus (variola virus, cowpox virus, vaccinia virus, molluscum contagiosum virus and orf) infections; adefovir against herpesvirus, hepadnavirus [human hepatitis B virus] and retrovirus [HIV type-1 and 2, simian immunodeficiency virus and feline immunodeficiency virus] infections; and tenofovir against both hepadna- and retrovirus infections. Cidofovir has been officially approved for the treatment of cytomegalovirus retinitis in AIDS patients, tenofovir disoproxil fumarate (Viread) for the treatment of HIV infections (i.e., AIDS) and adefovir dipivoxil for the treatment of chronic hepatitis B.

Antiviral drugs with specific activity against polyomavirus replication have not been developed in the past. This deficiency has become fully apparent with the emergence of polyomavirus-associated nephropathy in kidney-transplant recipients, with a prevalence rate of up to 10%. In most cases, high BK virus replication in tubular epithelial cells causes significant cytopathology, leading to permanently impaired renal allograft function and return to hemodialysis within 6-60 months. In 5-10% of allogenic bone marrow/hematopoietic stem cell transplant recipients, high-level BK virus replication in the ureter/bladder mucosa has been associated with postengraftment hemorrhagic cystitis, which appears to involve significant immunopathology. Thus, in view of the increasing clinical need, a number of drugs have been studied in small case series. We review the antiviral strategies explored to date and specifically discuss available in vivo and in vitro data on cidofovir, leflunomide, fluoroquinolones and intravenous immunoglobulins, regarding mechanism, administration, dosing and outcome and provide a perspective on future therapy options.

Cytomegalovirus (CMV) is the most common opportunistic viral infection to occur following solid-organ transplantation. This review will discuss the current strategies of management of CMV in solid-organ transplantation and their challenges. There are two principal approaches for preventing CMV disease in recipients of solid-organ transplants: prophylactic and pre-emptive. Ganciclovir is the most studied and used antiviral for both treatment and prevention, and is the first-line treatment for CMV infection and CMV disease in transplant recipients. There is no consensus regarding the most appropriate prevention method and the approach to CMV disease prevention differs among transplantation centers owing to the paucity of data comparing the two strategies head-to-head. Currently, the recommended treatment for CMV disease is intravenous ganciclovir.

Polyomaviruses are ubiquitous, species-specific viruses belonging to the family Papovaviridae. The two most commonly known human polyomaviruses, BK virus and JC virus were first described in the 1970s. Newer human polyomaviruses, namely KI polyoma virus, WU polyoma virus and Merkel cell polyoma virus were identified in the last five years. Most humans encounter BK and JC virus during childhood, causing mild illness. However, when reactivated or acquired in the immunocompromised host, BK and JC virus have been implicated in a number of human clinical disease states. BK is most commonly associated with renal involvement, such as ureteral stenosis, hemorrhagic cystitis and nephropathy. Less commonly, it is associated with pneumonitis, retinitis, liver disease and meningoencephalitis. JC virus is most well known for its association with progressive multifocal leukoencephalopathy, and is possibly implicated in the development of various human neoplasms. The following chapter will outline the basic virology, epidemiology and clinical manifestations of BK and JC virus and discuss relevant diagnostic and treatment options.

BK virus (BKV) and JC virus (JCV) are human polyomaviruses that cause asymptomatic latent infections. Under immunosuppression, BKV-associated nephropathy has been documented in Kuwait and elsewhere. Even though different BKV and JCV genotypes with distinct geographical distribution have been described, the genotype of polyomavirus detected in Kuwait is still unknown. The aim of this study was to determine the genotypes of BKV and JCV detected in renal transplant recipients. The detection of polyomavirus DNA was carried out in serum and urine samples of 200 post-transplant recipients during a 1-year follow-up period. Fifty-one (25.5%) post-transplant recipients were tested positive for polyomavirus DNA by semi-nested PCR. JCV DNA could be detected in 29 (57%) patients, and BKV DNA in 22 (43%) patients. In two renal transplant recipients, both BKV and JCV were detected. According to the Bayesian phylogenetic analysis of polyomavirus VP1 sequences, the majority of detected BKV sequences were most closely related to genotypes I and IV, whereas the majority of JCV sequences were most closely related to genotype 3. Polyomavirus VP1 sequences showed strong stability for up to 12 months in most patients; however, in one patient, an amino acid substitution in the BKV VP1 protein was identified over time. The results suggest a close relationship of BKV sequences with the Asian and European strains, and of JCV sequences with the African strains. Long follow-up studies are needed to investigate the association of polyomavirus polymorphism or genotypic shift with the development of nephropathy.

We prospectively screened 609 consecutive kidney (538) and kidney-pancreas (71) transplant recipients for BK viremia over a 4-year interval using polymerase chain reaction viral load detection and protocol kidney biopsies. We found that BK viremia is common at our center: total cases 26.7%, cases during first year 21.3% (mean 4 months), and recipients with ≥ 10 000 copies/ml 12.3%. We found few predictive clinical or demographic risk factors for any BK viremia or viral loads ≥ 10,000 copies/ml, other than prior treatment of biopsy confirmed acute rejection and/or higher immunosuppressive blood levels of tacrolimus (P = 0.001) or mycophenolate mofetil (P = 0.007). Viral loads at diagnosis (<10 000 copies/ml) demonstrated little impact on graft function or survival. However, rising copy numbers demand early reductions in immunosuppressive drug doses of at least 30-50%. Viral loads >185 000 copies/ml at diagnosis were predictive of BK virus-associated nephropathy (BKVAN; OR: 113.25, 95% CI: 17.22-744.6, P < 0.001). Surveillance for BK viremia and rapid reduction of immunosuppression limited the incidence of BKVAN to 1.3%. The addition of leflunomide or ciprofloxacin to immunosuppressive dose reduction did not result in greater rates of viral clearance. These data support the role of early surveillance for BK viremia to limit the impact on transplant outcome, although the most effective schedule for screening awaits further investigation.

The human BK polyomavirus (BKV) is the major cause of polyomavirus-associated nephropathy (PyVAN) 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.

The BK virus (BKV) can be reactivated with immunosuppressive treatment in renal allograft recipients, which can result in interstitial nephritis (BKV-associated nephropathy, BKVAN) and lead to renal allograft failure. Recently, leflunomide has been reported in some case series of BKVAN with favorable results. Most studies have included only adult patients, we herein report a pediatric case and include a literature review. The patient was a nine-yr-old female with end-stage renal disease due to hypoxic kidney injury. A deceased donor renal transplant was performed and good initial allograft function was achieved following treatment with prednisolone, tacrolimus and mycophenolate mofetil. The serum Cr level increased to 1.6 mg/dL over the following four-month period. A kidney biopsy revealed pathologic findings of acute cellular rejection and BK nephropathy. After methylprednisolone pulse therapy was administered to control acute rejection, the tacrolimus dose was reduced, and intravenous immunoglobulin treatment and leflunomide therapy were administered to control the BKVAN. Over the following 18 months, the viral load steadily decreased and remained below 100 copies/mL in the plasma. Leflunomide therapy in addition to a reduction of the immunosuppressive therapies resulted in a significant decline in the BK viral load without further deterioration of renal function.

The frequencies of 10 opportunistic DNA viruses were determined by multiplex real-time PCR in paired cerebrospinal fluid (CSF) and brain tissue of HIV-infected individuals. In the CSF, viruses were detectable in 45/55 cases: JC virus (JCV) in 62%, Epstein-Barr virus (EBV) in 44%, cytomegalovirus (CMV) in 25%, varicella-zoster virus (VZV) in 3.6%, herpes simplex virus 1 (HSV-1) in 1.8%, and human herpesvirus 6 (HHV-6) in 1.8% of cases. A single virus was detectable in 20 cases, 19 cases had coinfection with two viruses, and 6 cases were positive for three viruses. JCV was detectable in the CSF of 62% of cases and in 42% of brain tissues, with higher loads in progressive multifocal leukoencephalopathy (PML) (P < 0.05).

BK virus (BKV) infection in kidney transplant recipients is associated with progressive graft dysfunction and graft loss. Cidofovir, an antiviral agent with known nephrotoxicity, has been used in low doses to treat BKV infections. However, the systemic exposure and disposition of the low-dose cidofovir regimen are not known in kidney transplant recipients.

We investigated the pharmacokinetics (PK) of low-dose cidofovir (0.24 - 0.62 mg/kg) both without and with oral probenecid in 9 transplant patients with persistent BK viremia without nephropathy in a crossover design.

The mean estimated glomerular filtration rate (eGFR) of the study participants was 46.2 mL/min/1.73 m(2) (range: 17-75 mL/min/1.73 m(2) ). The contribution of active renal secretion to cidofovir total body clearance was assessed by evaluating the effect of probenecid on cidofovir PK. Maximum cidofovir plasma concentrations, which averaged approximately 1 μg/mL, were significantly below the 36 μg/mL 50% effective concentration in vitro for cidofovir against BKV. The plasma concentration of cidofovir declined with an overall disposition half-life of 5.1 ± 3.5 and 5.3 ± 2.9 h in the absence and in the presence of probenecid, respectively (P > 0.05).

Cidofovir clearance and eGFR were linearly related irrespective of probenecid administration (r(2) = 0.8 without probenecid; r(2) = 0.7 with probenecid). This relationship allows for the prediction of systemic cidofovir exposure in individual patients and may be utilized to evaluate exposure-response relationships to optimize the cidofovir dosing regimen for BKV infection.

BK virus (BKV) is known to be associated with nephropathy. Here, we investigated the relationships between BKV levels, T-cell activation, and kidney function in kidney transplant recipients.

In renal transplant patients and controls, urine BKV levels were detected by quantitative real-time PCR, and the percentage of activated T lymphocytes in blood was determined by flow cytometry. The correlations between viral load, activated T cell percentage, and renal function were determined.

Urine BKV viral loads and the activated T cell percentage were significantly elevated in transplant recipients. Correlational analysis indicated that transplant recipients that had BKV levels of more than 10(6) copies/mL and an activated T lymphocyte percentage of less than 20% were likely to have poor renal function.

Urine BKV levels and the percentage of activated T lymphocytes can be used as clinical indices to optimize the dosage of immunosuppressive drugs.

Viral infections remain a significant cause of morbidity and mortality following renal transplantation. The pediatric cohort is at high risk of developing virus-related complications due to immunological naiveté and the increased alloreactivity risk that requires maintaining a heavily immunosuppressive environment. Although cytomegalovirus is the most common opportunistic pathogen seen in transplant recipients, numerous other viruses may affect clinical outcome. Recent technological advances and novel antiviral therapy have allowed implementation of viral and immunological monitoring protocols and adoption of prophylactic or preemptive treatment approaches in high-risk groups. These strategies have led to improved viral infection management in the immunocompromised host, with significant impact on outcome. We review the major viral infections seen following kidney transplantation and discuss strategies for preventing and managing these pathogens.

This study investigated the age-related prevalence of a prior polyoma BKV infection at the time of transplantation and association with subsequent development of BKV viremia. We measured BKV-specific antibody titers in stored serum samples obtained before transplantation in 94 pediatric kidney transplant recipients (in a single-center, retrospective analysis) and 40 matched donors from 1986 to 2007. Titers were categorized as LOW or HIGH serostatus at titers of ≤ 1:2560 and ≥ 1:10 240, respectively. Of these, 36 recipients transplanted since 2002 were prospectively screened for BKV viremia. Seventeen percent of recipients aged 0-6 yr had HIGH BKV serostatus compared with 73% of older recipients (p < 0.002). The prevalence of HIGH donor BKV serostatus was 73%. Five prospectively screened patients (14%) developed early BKV viremia, and an additional 4 (11%) had late onset of BKV viremia. There were three cases (8%) of BKVAN. LOW BKV serostatus was significantly associated with early BKV viremia (p = 0.02). Donor HIGH to recipient LOW (HIGH/LOW) had the highest risk of BKV viremia (4/7; 57%), compared with LOW/LOW (0/3; 0%) and recipient HIGH (1/26; 4%) (p = 0.004). BKV IgG titers are low in young pediatric kidney transplant recipients, and LOW BKV serostatus is associated with an increased risk of early BKV infection post-transplant, particularly in the context of donor with HIGH BKV serostatus.

The BK virus, a DNA virus from the Polyomavirus group, represents an opportunistic infection of immunosuppressed transplant recipients. Though the virus was discovered approximately 40 years ago, the emergence of BK virus nephropathy since 1995 onwards, with associated high graft loss rates, has revolutionized renal transplantation medicine. Kidney transplant professionals realized that the consequences of over-immunosuppression were as severe as the consequences of under-immunosuppression and we entered the era of immunosuppressive minimization. Despite this recognition, the optimal testing type for BK virus infections and frequency of testing are hotly debated. Similarly, optimal treatment strategies remain sources of intense controversy. The authors review the current strategies of screening, diagnosis, and possible treatment, and also review the amount and quality of evidence in favor or against. Similarities and differences between cytomegalovirus, Epstein-Barr virus, and BV virus, the three major viral infections in kidney transplantation, are highlighted.

Polyomavirus-associated nephropathy (PVAN) is an increasing cause of renal allograft dysfunction, but the optimal management of immunosuppression for these patients is unclear. We examined the clinical course of 58 patients with biopsy-proven PVAN diagnosed from 1997 to 2008 at Johns Hopkins Medical Institutions. Immunosuppression management was analyzed as 2 different immunosuppression reduction strategies, the first centered on eliminating a single immunosuppressive drug and reducing the doses of all other immunosuppressive drugs (Strategy A, n = 40), compared with the second, centered on reducing the doses of all immunosuppressive drugs and eliminating none (Strategy B, n = 18). Primary outcome was graft failure, defined as a 50% reduction in estimated glomerular filtration rate, or the need for dialysis within 2 years of PVAN diagnosis. Graft failure developed in 17 (29%) patients during follow-up. In unadjusted and adjusted Cox models, both strategies of immunosuppression reduction had similar efficacy in preventing graft failure (hazard ratio [HR], 0.61; 95% confidence interval, 0.18-2.06; p = 0.43). Rejection after PVAN occurred in 24 of 58 patients and was associated with a 3-fold higher risk of graft failure (HR, 2.99; p = 0.005). Ancillary therapies (cidofovir or leflunomide) were associated with a trend toward faster clearance of viremia (p = 0.65) but were not predictive of outcome.In conclusion, the 2 strategies of immunosuppression reduction had similar efficacy in preventing graft failure. Post-PVAN rejection leads to graft failure. Early repeat allograft biopsy should be considered in the management of PVAN with persistent graft dysfunction.