mycophenolic-acid and Polyomavirus-Infections

JC polyomavirus-associated nephropathy (JC-PVAN) is a rare but challenging cause of renal dysfunction. We report JC-PVAN in a renal allograft recipient and highlight the obstacles in definitive diagnosis of this disease entity. A deceased-donor renal transplant recipient was diagnosed with JC polyomavirus nephritis 4 years after transplantation. Immunosuppressive agents were subsequently reduced, resulting in an initial stabilization of renal function. We present this interesting case and discuss the challenges with diagnosing and treating this rare entity.

Topics: Biopsy; BK Virus; Creatinine; Graft Rejection; Humans; Immunoglobulins, Intravenous; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Isoxazoles; JC Virus; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Leflunomide; Male; Middle Aged; Mycophenolic Acid; Nephritis; Polymerase Chain Reaction; Polyomavirus Infections; Sirolimus; Tacrolimus; Transplantation, Homologous; Viremia

The increasing incidence of BK-associated nephropathy following kidney transplantation has prompted an examination of strategies for risk reduction and management through immunosuppression manipulation. Evidence from retrospective and prospective studies suggests that BK viruria and viremia, and the need for BK virus treatment, are higher with tacrolimus than cyclosporine. Combined therapy with tacrolimus and mycophenolic acid may be associated with a particularly higher risk of BK infection, but data are conflicting as to whether mycophenolic acid per se is an independent risk factor. The incidence of BK-related events may be reduced in patients receiving mTOR inhibitors (everolimus or sirolimus) with cyclosporine vs a calcineurin inhibitor with mycophenolic acid. De novo immunosuppression regimens that avoid rabbit antithymocyte globulin and tacrolimus, particularly tacrolimus with mycophenolic acid, may be advantageous, whereas low-exposure cyclosporine with an mTOR inhibitor appears a favorable option. Routine screening for BK infection during the first 2 years posttransplant is recommended to allow preemptive modification of the immunosuppressive regimen. In patients at high risk of BK virus infection, appropriate de novo immunosuppression or very early conversion to an mTOR inhibitor to facilitate reduction or discontinuation of calcineurin inhibitors or antimetabolites should be considered. Extensive further research into optimal avoidance, screening, and treatment strategies is required.

Topics: Antilymphocyte Serum; BK Virus; Calcineurin Inhibitors; Glucocorticoids; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Polyomavirus Infections; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases; Tumor Virus Infections; Virus Activation; Virus Replication

New classes of agents have sequentially increased the specificity of post-transplant immunosuppression, leading to profound improvements in success rates after renal transplantation. The next era will focus on increased long-term survival rates through optimal use of existing agents and the rational development of drugs based on prior identification of specific immunologic targets. Conventionally, long-term outcomes after kidney transplantation have been assessed by surrogate markers, notably acute rejection, but graft-threatening complications such as development of new-onset diabetes mellitus and polyomavirus nephropathy must be addressed if long-term survival rates are to be improved. Mycophenolic acid therapy must be administered optimally to ensure that adequate exposure is achieved in the immediate post-transplant period and, subsequently, by avoiding underdosing due to gastrointestinal events. Chronic allograft nephropathy remains a major concern, and protocol-led, reliable monitoring strategies are essential to enable early intervention, for example, through introduction of proliferation signal inhibitor therapy with concomitant calcineurin inhibitor reduction or withdrawal. The range of immunosuppressive regimens now available and in development, together with improved assessment of patients' risk profiles for immunologic events and comorbid disease, offers the opportunity for further individualization of immunosuppression after renal transplantation.

Topics: Biomarkers; Calcineurin Inhibitors; Diabetes Mellitus; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Polyomavirus Infections; Survival Rate

This is a randomized trial (ATHENA study) in de novo kidney transplant patients to compare everolimus versus mycophenolic acid (MPA) with similar tacrolimus exposure in both groups, or everolimus with concomitant tacrolimus or cyclosporine (CsA), in an unselected population. In this 12-month, multicenter, open-label study, de novo kidney transplant recipients were randomized to everolimus with tacrolimus (EVR/TAC), everolimus with CsA (EVR/CsA) or MPA with tacrolimus (MPA/TAC), with similar tacrolimus exposure in both groups. Non-inferiority of the primary end point (estimated glomerular filtration rate [eGFR] at month 12), assessed in the per-protocol population of 338 patients, was not shown for EVR/TAC or EVR/CsA versus MPA/TAC. In 123 patients with TAC levels within the protocol-specified range, eGFR outcomes were comparable between groups. The mean increase in eGFR during months 1 to 12 post-transplant, analyzed post hoc, was similar with EVR/TAC or EVR/CsA versus MPA/TAC. The incidence of treatment failure (biopsy proven acute rejection, graft loss or death) was not significant for EVR/TAC but significant for EVR/CsA versus MPA/TAC. Most biopsy-proven acute rejection events in this study were graded mild (BANFF IA). There were no differences in proteinuria between groups. Cytomegalovirus and BK virus infection were significantly more frequent with MPA/TAC. Thus, everolimus with TAC or CsA showed comparable efficacy to MPA/TAC in de novo kidney transplant patients. Non-inferiority of renal function, when pre-specified, was not shown, but the mean increase in eGFR from month 1 to 12 was comparable to MPA/TAC.

Topics: Adult; Aged; Allografts; Calcineurin Inhibitors; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Everolimus; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polyomavirus Infections; Standard of Care; Tacrolimus; Treatment Failure

We sought to determine whether conversion from tacrolimus/mycophenolate mofetil (TAC-MMF) into tacrolimus/mTOR inhibitor (TAC-mTOR) immunosuppression would reduce the incidences of BK and CMV viremia after kidney/pancreas (KP) transplantation.. In this single-center review, the TAC-mTOR cohort (n = 39) was converted at 1 month post-transplant to an mTOR inhibitor and reduced-dose tacrolimus. Outcomes were compared to a cohort of KP recipients (n = 40) maintained on TAC-MMF.. At 3 years post-transplant, KP survivals and incidences of kidney/pancreas rejection were equivalent between mTOR and MMF-treated cohorts. (P = ns). BK viremia-free survival was better for the mTOR vs MMF-treated group (P = .004). In multivariate analysis, MMF vs mTOR immunosuppression was an independent risk factor for BK viremia (hazard ratio 12.27, P = .02). Similarly, mTOR-treated recipients displayed better CMV infection-free survival compared to the MMF-treated cohort (P = .01). MMF vs mTOR immunosuppression (hazard ratio 18.77, P = .001) and older recipient age (hazard ratio 1.13 per year, P = .006) were independent risk factors for CMV viremia. Mean estimated GFR and HgbA1c levels were equivalent between groups at 1, 2, and 3 years post-transplantation.. Conversion from TAC/MMF into TAC/mTOR immunosuppression after KP transplantation reduced the incidences of BK and CMV viremia with an equivalent risk of acute rejection and similar renal/pancreas function.

Topics: Adult; BK Virus; Cytomegalovirus; Cytomegalovirus Infections; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Polyomavirus Infections; Postoperative Complications; Prognosis; Retrospective Studies; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases; Tumor Virus Infections; Viremia; Young Adult

BK virus (BKV) is a significant post-transplant infection. Mammalian target of rapamycin inhibitors (mTORis) reduce BKV large T antigen expression in vitro and are associated with lower rates of BKV infection when used as de novo immunosuppression in clinical studies.. Forty patients were enrolled and randomized in a 1:1 manner; 11 (55%) and 8 patients (40%) reached the primary endpoint in the everolimus group and the MMF group, respectively (P = .53). Of those with BK viremia at the time of enrollment, 8 of 16 (50%) and 5 of 15 (33.3%) cleared the viremia by month 3 in the everolimus conversion and MMF dose reduction groups, respectively (P = .47).. Conversion from MMF to everolimus in BKV infection demonstrated a trend toward improved viral clearance but did not reach statistical significance.

Topics: Adult; Aged; BK Virus; Drug Substitution; Everolimus; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Polyomavirus Infections; Postoperative Complications; Prospective Studies; Substance Withdrawal Syndrome; Tacrolimus; Tumor Virus Infections; Viremia

This provides the long-term patient/graft survival and outcome of BK viremia and BK virus allograft nephropathy (BKVAN) in renal transplant recipients in the setting of intensive monitoring and preemptive of reduction of immunosuppression. Quantitative BKV DNA PCR and urinary cytology surveillance were performed regularly after transplantation in 229 kidney recipients. Patients with BK viremia and BKVAN were treated with 30-50% reduction in doses of tacrolimus and/or mycophenolate mofetil and were monitored for BKV every 3-6 months. All the patients were followed for 5 years. Overall 5-year patient and graft survival were 95.6% and 92.1%, respectively, and independent of presence of decoy cells, BK viruria, viremia, or BKVAN. After reduction of immunosuppression, BK viremia (n = 38) resolved in 100% of patients, without increased acute rejection. Recurrent BK viremia was not observed in viremic patients without BKVAN (n = 30). All BKVAN patients (n = 7, 3.1%) cleared viremia with a mean time of 5.9 months (range 1-15 months) and manifested no decline in estimated glomerular filtration rate from 1 month to 5 years after transplantation. Viral monitoring and preemptive reduction of immunosuppression resulted in the successful resolution of BK viremia and BKVAN with excellent graft survival and renal function at 5 years.

Topics: Adult; BK Virus; DNA, Viral; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polymerase Chain Reaction; Polyomavirus Infections; Survival Analysis; Tacrolimus; Transplant Recipients; Treatment Outcome; Urine; Viral Load; Viremia

Polyomavirus-associated graft nephropathy (PAN) has emerged as a significant risk factor for kidney graft loss. We analyzed intracellular cytokine responses for possible protective versus permissive immunologic effects on BK-virus replication. One hundred five renal transplant patients included in a prospective single-center study were randomized to receive cyclosporine mycophenolate mofetil (MMF) (CM: n = 31), tacrolimus (Tac)/MMF (TM: n = 32) or Tac/MMF with conversion to everolimus (TErl; n = 32). Ten patients were not randomized (NR) due to contraindications to MMF. The immunosuppressive therapy was monitored pre- and posttransplantation at 4, 12, and 24 months using triple fluorescence flow cytometry for intracellular interleukin (Il)-2 Il-4 and interferon (IFN)-γ production in phorbol myristate acetate- and lipopolysaccharide- stimulated lymphocyte cultures. BK viremia screening was performed by reverse-transcriptase polymerase chain reaction testing on days 0, 14, 30, 60, 90, 120, 180, 270, 360, and 720. Seven of 105 (6.7%) patients developed biopsy-proven PAN (CM: n = 1, TM: n = 3, TErl: n = 2, NR: n = 1), among whom 4 lost their grafts (TM: n = 1, TErl: n = 2, NR: n = 1). Twenty-one of 105 (20.0%) patients had documented BK viremia. BK viremia which preceded PAN in all cases, was significantly associated with TM immunosuppression: 4/31 (12.9%) CM: 11/32 (34.4%) TM; 5/32 (15.6%) TErl, and 1/10 (10.0%) NR patients (P = .034). BK-viremic patients showed significantly diminished CD8(+) T-cell Il-2 production at 120 days (P = .011) and 1 year posttransplantation (P = .014) compared with non-BK-viremic patients. Patients with PAN displayed significantly lower CD4(+) T-cell Il-4 responses at 1 and 2 years after transplantation (1 year: P = .007; 2 years: P = .001) with diminished IFN-γ responses at 1 year after transplantation (P = .011). Our analysis showed the incidence of BK viremia to be increased among patients with defective cytotoxic CD8(+) T-cell -dependent immune reactivity. Recipients who progressed from BK viremia to overt PAN showed an additional immunologic defect in CD4(+) T-cell function. Patients on a Tac- plus MMF-based immunosuppression were at higher risk to develop BK viremia.

Topics: BK Virus; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cyclosporine; Everolimus; Flow Cytometry; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Polyomavirus Infections; Prospective Studies; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Sirolimus; Tacrolimus; Viremia

BK polyomavirus infection has been reported in 10% to 60% of renal transplant recipients with progression to BK nephropathy (BKN) occurring in 1% to 5% of patients. Graft loss occurs in up to 60% of renal transplant recipients with BKN. Because BK polyomavirus infection is believed, in part, to be a manifestation of overimmunosuppression, the current standard of care involves the reduction of immunosuppressants. This strategy has been associated with clearance of viral load, preservation of renal function, and improvement in graft survival; however, this may come at a risk of rejection. A safe and effective immunosuppressive agent that does not predispose to viral infection is needed in transplantation.. In a phase 2, proof-of-concept, randomized, open-label, parallel-group, 6-month study in renal transplant patients, FK778 (an investigational immunosuppressant from the malononitrilamides class) was compared with the current standard of care (reduction of immunosuppression) for treatment of newly diagnosed or untreated BKN, which was confirmed by renal biopsy.. Demographic characteristics were similar between the two groups, except there were numerically more females in the FK778 group than in the standard care group. Although the treatment with FK778 decreased BK viral load in this study, it was associated with a less favorable rejection profile and renal function and a higher incidence of serious adverse events compared with reduction of immunosuppression.. Data from this study are consistent with the findings of previous studies that found no benefit of drug therapy in the treatment of BKN in kidney transplant recipients.

Topics: Algorithms; Alkynes; Creatinine; Cyclosporine; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Isoxazoles; Kidney Transplantation; Mycophenolic Acid; Nitriles; Patient Compliance; Polyomavirus Infections; Sirolimus; Tacrolimus; Time Factors; Viral Load

Nocardiosis is a life-threatening infection in immunocompromised patients. The prevalence of the disease ranges from 2.3% to 5% in renal allograft recipients. Here, we describe a case of BK nephropathy associating with nocardiosis with successful recovery. The 54-year-old male patient had end-stage kidney disease due to diabetic nephropathy associated with diabetic retinopathy, hypertension, and dyslipidemia. He started hemodialysis in October 2017; 2 years later, he underwent a deceased donor kidney transplant with 2 HLA mismatches and high panel reactive antibodies. He received desensitization with intravenous immunoglobulin and rituximab, received thymoglobulin as induction, and was maintained on prednisolone, mycophenolate mofetil, and tacrolimus. His serum creatinine decreased to a nadir of 90 μmol/L. He developed graft dysfunction, which was proven to be due to BK nephropathy. Therefore, mycophenolate mofetil was replaced with leflunomide in addition to intravenous immunoglobulin therapy. Ten months later, he had an accidental fall and sought an orthopedic evaluation. Magnetic resonance imaging of the lumbar spine and pelvis revealed lumbar spondylosis, avascular necrosis of the femoral head, and obturator muscle abscess. He was explored surgically, but the surgeon found no abscess or avascular hip necrosis. The patient's blood grew Nocardia, and he was readmitted and started imipenem and linezolid empirically. Brain and chest computed tomography scans ruled out any central nervous system or pulmonary involvement, but a bone scan revealed osteomyelitis of the right superior pubic ramus and prepubic swelling, which was confirmed by computed tomography to be an abscess in both obturator externus and internus. He continued the same antibiotics for 6 months based on culture and sensitivity. At follow-up, the patient has shown stable graft function (creatinine 155 μmol/L) with improved BK viremia with immunosuppression minimization. In renal transplant recipients, successful management of combined BK nephropathy and nocardiosis was feasible with minimization of immunosuppression and proper antimicrobial therapy.

Topics: Abscess; BK Virus; Creatinine; Graft Rejection; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Nocardia Infections; Polyomavirus Infections; Treatment Outcome; Tumor Virus Infections

Human polyomavirus BK (BKPyV) is the etiologic agent of polyomavirus-associated nephropathy, a leading cause of kidney transplant dysfunction. Because of the lack of antiviral therapies, immunosuppression minimization is the recommended treatment. This strategy offers suboptimal outcomes and entails a significant risk of rejection. Our aim was to evaluate the effect of different immunosuppressive drugs (leflunomide, tacrolimus, mycophenolic acid, sirolimus, and everolimus) and their combinations in an in vitro model of BKPyV infection.. Human renal tubular epithelial cells were infected with BKPyV and treated with leflunomide, tacrolimus, mycophenolic acid, sirolimus, and everolimus, administered alone or in some combination thereof. Viral replication was assessed every 24 hours (up to 72 hours) by BKPyV-specific quantitative real-time polymerized chain reaction for the VIRAL PROTEIN 1 sequence in cell supernatants and by western blot analysis targeting the viral protein 1 and the glyceraldehyde 3-phosphate dehydrogenase on total protein lysates. Results were described as viral copies/mL and compared between treatments at any prespecified time point of the study.. The highest inhibitory effects were observed using leflunomide or everolimus plus mycophenolic acid (mean BKPyV replication log reduction 0.28). The antiviral effect of everolimus persisted when it was used in combination with tacrolimus (mean BKPyV replication log reduction 0.27).. Our experience confirms that everolimus has anti-BKPyV properties and prompts future research to investigate possible mechanisms of action. It also provides a rational basis for targeted clinical trials evaluating alternative immunosuppressive modification strategies.

Topics: Antiviral Agents; BK Virus; Everolimus; Humans; Immunosuppressive Agents; Kidney Transplantation; Leflunomide; Mycophenolic Acid; Polyomavirus Infections; Sirolimus; Tacrolimus; Tumor Virus Infections; Viral Proteins

A 66-year-old Chinese man underwent a deceased donor kidney transplantation. Induction-immunosuppressive protocol consisted of basiliximab (BAS) and methyl prednisolone (MP), followed by maintenance immunosuppression with cyclosporin (CsA), mycophenolate mofetil (MMF), and prednisone (PED). The patient's post-transplantation course was almost uneventful, and the graft was functioning well [serum creatinine (Scr) 2.15 mg/dL]. The MMF and CsA doses were decreased 1-month post-operative as the BK virus activation was serologically positive. His Scr was elevated to 2.45 mg/dL 45 days after the transplant. A graft biopsy showed BKV nephropathy (BKVN) and acute T cell-mediated rejection (TCMR) Banff grade IIA (I2, t2, ptc2, v1, c4d1, g0, and SV40 positive). The conventional anti-rejection therapy could deteriorate his BKVN, therefore, we administered BAS to eliminate activated graft-infiltrating T cells and combined with low-dose steroid. He responded well to the therapy after two doses of BAS were given, and the kidney graft status has been stable (recent Scr 2.1 mg/dL).

Topics: Aged; Basiliximab; BK Virus; Creatinine; Cyclosporine; Graft Rejection; Humans; Kidney Diseases; Kidney Transplantation; Male; Mycophenolic Acid; Polyomavirus Infections; Prednisolone; Prednisone; T-Lymphocytes

Some studies have suggested mizoribine (MZR) could inhibit the replication of BK polyomavirus (BKPyV). The purpose of this study was to explore whether conversion from mycophenolate mofetil (MMF) to MZR in the early stages of BKPyV infection can improve kidney allograft prognosis.. Twenty-one kidney transplant recipients with BKPyV viruria/viremia and ten with BK polyomavirus-associated allograft nephropathy (BKPyVAN) received MZR conversion therapy were retrospectively identified. The clearance rate of urine and blood BKPyV DNA, change of serum creatinine (SCr), uric acid (UA), hemoglobin (HB), white blood cell (WBC), lymphocyte ratio, platelet (PLT), routine urinalysis, panel reactive antibody (PRA), and gastrointestinal disorders during follow-up of the 2 groups were evaluated and compared.. After MZR conversion therapy, the clearance rate of urine and blood viral load in BKPyV viruria/viremia group were 85.7 and 100 %, while that in BKPyVAN were 40 and 87.5 %, respectively. Stable SCr were observed in all cases of BKPyV viruria/viremia group, while that of BKPyVAN was only 40 % (P < 0.001) and one even progressed to end-stage renal disease. The results of routine urinalysis in the two groups showed no significant changes before and after MZR conversion therapy. However, in BKPyV viruria/viremia group, four cases developed acute rejection and one had positive PRA-II but no donor specific antibody, requiring conversion back to MMF. Hyperuricemia was the common adverse effect of MZR.. Conversion from MMF to MZR could help clear BKPyV infection. As compared to BKPyVAN, patients who underwent initiation of MZR conversion therapy in the early stages of BKPyV infection maintained stable allograft function. Prospective studies with larger sample size are needed to ascertain this preliminary finding.

Topics: Adult; Antibiotics, Antineoplastic; BK Virus; China; Drug Substitution; Female; Humans; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polyomavirus Infections; Postoperative Complications; Prognosis; Retrospective Studies; Ribonucleosides; Tumor Virus Infections; Young Adult

The clinical course and outcomes of immunocompromised patients, such as transplant recipients, with COVID-19 remain unclear. It has been postulated that a substantial portion of the disease burden seems to be mediated by the host immune activation to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein, we present a simultaneous heart-kidney transplant (SHKT) recipient who was hospitalized for the management of respiratory failure from volume overload complicated by failure to thrive, multiple opportunistic infections, and open non-healing wounds in the setting of worsening renal dysfunction weeks prior to the first case of SARS-CoV-2 being detected in the state of Connecticut. After his third endotracheal intubation, routine nucleic acid testing (NAT) for SARS-CoV-2, in anticipation of a planned tracheostomy, was positive. His hemodynamics, respiratory status, and ventilator requirements remained stable without any worsening for 4 weeks until he had a negative NAT test. It is possible that the immunocompromised status of our patient may have prevented significant immune activation leading up to clinically significant cytokine storm that could have resulted in acute respiratory distress syndrome and multisystem organ failure.

Topics: Antibiotics, Antineoplastic; Bacteremia; BK Virus; Cardiomyopathy, Dilated; Cardiotoxicity; COVID-19; COVID-19 Nucleic Acid Testing; Doxorubicin; Graft Rejection; Gram-Positive Bacterial Infections; Heart Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Incidental Findings; Kidney Failure, Chronic; Kidney Transplantation; Male; Malnutrition; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Mycophenolic Acid; Opportunistic Infections; Polyomavirus Infections; Postoperative Complications; Prednisone; Renal Dialysis; SARS-CoV-2; Staphylococcal Infections; Surgical Wound Infection; Tacrolimus; Tracheostomy; Tumor Virus Infections; Vancomycin-Resistant Enterococci; Viremia; Water-Electrolyte Imbalance

BK virus-associated nephropathy (BKVAN) is a relatively common cause of renal dysfunction in the first six months after renal transplantation. It arises from reactivation of the latent and usually harmless BK virus (BK virus) due to immunosuppression and other factors including some that are unique to renal transplantation such as allograft injury. BKVAN is much rarer in non-renal solid organ transplantation, where data regarding diagnosis and management are extremely limited.. We report a case of a 58-year-old man found to have worsening renal dysfunction nine months after bilateral sequential lung transplantation for chronic obstructive pulmonary disease (COPD). He had required methylprednisolone for acute allograft rejection but achieved good graft function. Urine microscopy and culture and renal ultrasound were normal. BK virus PCR was positive at high levels in urine and blood. Renal biopsy subsequently confirmed BKVAN. The patient progressed to end-stage renal failure requiring haemodialysis despite reduction in immunosuppression, including switching mycophenolate for everolimus, and the administration of intravenous immunoglobulin (IVIG).. This very rare case highlights the challenges presented by BK virus in the non-renal solid organ transplant population. Diagnosis can be difficult, especially given the heterogeneity with which BKV disease has been reported to present in such patients, and the optimal approach to management is unknown. Balancing reduction in immunosuppression against prevention of allograft rejection is delicate. Improved therapeutic options are clearly required.

Topics: BK Virus; DNA, Viral; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kidney Transplantation; Lung Transplantation; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Polyomavirus Infections; Pulmonary Disease, Chronic Obstructive; Tumor Virus Infections

Immunosuppressive drug tapering is currently the recommended treatment of BK virus (BKV) viremia after kidney transplantation; however, its exact modalities remain unclear. We retrospectively compared two consecutive strategies in 111 patients with sustained viremia: a gradual monitoring/tapering group (GT, n = 57) before 2012 and a rapid monitoring/tapering group (RT, n = 54) after 2012. At viremia diagnosis, the dose of mycophenolic acid (MPA) and tacrolimus levels (T

Topics: Adult; Aged; BK Virus; Drug Administration Schedule; Female; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Polyomavirus Infections; Retrospective Studies; Tacrolimus; Viremia

The immunosuppressant agents in kidney transplantation (KT) may lead to various complications such as opportunistic infections and malignancies. BK virus associated nephropathy is a significant complication following KT, and it can result in graft failure. BK virus causes tubulointerstitial nephritis, ureter stenosis, and even graft failure in KT recipients with impaired immune system. We described a 63-year-old woman, who was a hepatitis C carrier and on dialysis for 22 years before KT, who received cadaveric-donor KT 2 years previously. She reported decreasing urine output and general weakness. The serum creatinine level was slightly increased from 2.94 to 4.38 mg/dL.. Immunosuppressant medications including prednisolone, everolimus, cyclosporin, and mycophenolate sodium were continued as maintenance therapy post KT. Kidney biopsy was performed due to deterioration of graft function.. The kidney biopsy showed consistent results with early-stage polyomavirus nephropathy, characterized by focal viral cytopathic changes with positive immunohistochemical signals and mesangial proliferative glomerulonephritis, immune-complex-mediated (Fig 1 and Fig 2). Negative C4d staining at peritubular capillary was reported. The dosage of mycophenolate sodium was tapered from 720 to 360 mg daily and that of everolimus increased from 0.5 to 1.0 mg daily due to BK viral infection with BK nephropathy. The serum creatinine level was 2.75 mg/dL after treatment.. Early detection of BK nephropathy and decreasing immunosuppressant agents are the mainstay of treatment. Substituting leflunomide for mycophenolate sodium and increasing dosage of everolimus has been proposed to solve BK nephropathy. We presented that the use of leflunomide in such situation is in a timely manner.

Topics: BK Virus; Everolimus; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Leflunomide; Middle Aged; Mycophenolic Acid; Nephritis, Interstitial; Opportunistic Infections; Polyomavirus Infections; Transplantation, Homologous; Tumor Virus Infections

BK virus-associated nephropathy (BKVAN) is a significant cause of allograft dysfunction and failure in kidney transplant recipients. Early detection and proper adjustment of immunosuppression is the best method for treatment of this condition and to improve long-term allograft outcome. Here, we reported the prevalence and risk factors of BK virus (BKV) infection in our population.. We retrospectively reviewed kidney transplant recipients at Siriraj Hospital between January 2012 and December 2015 who had been investigated using real-time polymerase chain reaction BK viral load. BKV infection including BK viruria, BK viremia, and BKVAN had been reported.. Protocol screening of BKV following with adjusted immunosuppressive regimens should be established for preventing allograft loss in BKVAN especially in the first year after transplantation and in patients who receive more than 1 g of MPA per day. Urinary BK viral load is the early marker for prediction of BK viremia, which leads to BKVAN.

Topics: Adult; BK Virus; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polyomavirus Infections; Prevalence; Retrospective Studies; Thailand; Tumor Virus Infections

BK virus allograft nephropathy (BKVAN) is a graft-threatening complication after kidney transplantation. Current consensus regarding the prevention of BKVAN is to screen for BK viremia and to treat sustained BK viremia through reducing immunosuppression. This study assessed the effect of conversion from mycophenolates to mizoribine (MZR) on the prevention of BK viremia in kidney transplant recipients.. Fifty kidney transplant recipients with high levels BK viruria were enrolled, including 11 recipients with BK viremia. After 6 months of MZR therapy, only 3 recipients still had high levels of BK viruria. The clearance rate of BK viremia was 100%. One episode of acute rejection occurred (2.0%) and was reversed by steroid administration. The serum uric acid level of the recipients was similar before and after switching to MZR, but the proportion of recipients receiving uric acid-reducing drugs increased significantly after 3 months of MZR therapy (19/50 vs 31/50; P = .02). No new cases of BK viremia were observed after conversion to MZR.. Conversion from mycophenolates to MZR in kidney transplant recipients with sustained high levels of BK viruria was associated with reduction of BK viruria and clearance of BK viremia. This may be an effective approach to prevent BK viremia and BKVAN.

Topics: Adult; BK Virus; Female; Humans; Immunocompromised Host; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polyomavirus Infections; Postoperative Complications; Prospective Studies; Ribonucleosides; Transplant Recipients; Transplantation, Homologous; Tumor Virus Infections; Viremia

The immunosuppressive agents mycophenolate acid (MPA) and tacrolimus (Tac) are associated with a higher incidence of BK polyomavirus nephropathy (BKPyVAN). In this observational retrospective cohort study, the frequency of BK polyomavirus (BKPyV) complications over a 24-month period was studied.. 358 renal transplant recipients (RTR) treated with MPA, with either cyclosporine A (CsA) (CsAM group) or Tac (TacM group) and mostly prednisolone, were included.. Incidence of BKPyV-viremia was not significantly different between the CsAM (n = 42/191) (22.0%) and the TacM (n = 36/167) (21.6%) group. Biopsy proven BKPyVAN occurred more often in the TacM group (6.6%) versus the CsAM group (2.1%) (p = 0.03). Longitudinal data analysis showed a significant earlier decline of viral load in plasma in the CsAM group compared to the TacM group (p = 0.005). The incidence of biopsy proven acute rejection (BPAR) was significantly higher in the CsAM (19.9%) compared to the TacM (10.8%) (p = 0.02) group. Graft loss, estimated glomerular filtration rate and mortality rate did not differ in both treatment groups.. In conclusion, this study shows that immunosuppressive treatment with Tac and MPA compared to CsA and MPA is associated with a lower incidence of BPAR, but at the cost of an increased risk of developing BKPyVAN in the first two years post-transplant.

Topics: Adult; BK Virus; Cyclosporine; Female; Genotype; Graft Rejection; Host-Pathogen Interactions; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Outcome Assessment, Health Care; Polyomavirus Infections; Retrospective Studies; Tacrolimus; Transplant Recipients; Tumor Virus Infections

Immunosuppression using everolimus (EVR) plus low-dose tacrolimus (Tac) is commonly used in organ transplantation. EVR has potential antiviral effects. Herein, the long-term outcomes and impacts of Tac-EVR on the BK virus are reported in ABO-incompatible kidney-transplant recipients. The initial immunosuppressive regimen combined steroids, Tac, and mycophenolic acid (MPA). At a median of 141 (34-529) days post-transplantation, seven stable ABO-incompatible kidney-transplant recipients were converted from MPA to EVR because of active BK replication, and compared with a reference group of fourteen ABO-incompatible patients receiving classical Tac plus MPA. At 1 month before conversion, at 1, 3 months after, and at last follow-up, clinical and biological parameters were monitored. The median time from conversion to the last follow-up was 784 (398-866) days. Conversion to EVR caused no change to rejection episodes or immunological status (isoagglutinin titers, anti-HLA antibodies). At last follow-up, median eGFR was similar in the Tac-MPA versus Tac-EVR group (40 [range: 14-56] vs. 54.5 ml/min/1.73 m(2) [range: 0-128], P = 0.07). The major adverse event was dyslipidemia. Interestingly, conversion from MPA to EVR decreased BK viral load in five patients. ABO-incompatible kidney-transplant recipients with an active BK virus infection may benefit from conversion to EVR.

Topics: ABO Blood-Group System; Adult; Aged; BK Virus; Everolimus; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Polyomavirus Infections; Retrospective Studies; Tacrolimus; Tumor Virus Infections; Viremia; Young Adult

BK polyomavirus (BKV) infection and BKV nephropathy (BKVN) are risk factors for allograft function and survival.. We retrospectively analyzed BK viremia and BKVN in 348 patients who received a kidney transplantation donated after brain death (n=232) or living donation (n=116) between 2008 and 2013. A total of 266 patients were treated with standard immunosuppression consisting of basiliximab induction, calcineurin inhibitor (CNI), and mycophenolic acid (MPA, n=219) or everolimus (n=47); 82 patients received more intense immunosuppression with lymphocyte depletion, CNI and MPA (n=38) or everolimus (n=44).. BK viremia occurred in 33 (9.5%) patients in the first year and in 7 (2.0%) recipients in the second year after transplantation. BKVN occurred in 4 (1.1%) patients in the first year. Donor and recipient age, diabetes, previous transplantation, and type of transplantation (donated after brain death vs living donation) were not risk factors (P>.05). BK incidence did not differ depending on induction or maintenance immunosuppression.. Incidence of BK viremia is independent of recipient characteristics, type of transplantation as well as induction and maintenance immunosuppression.

Topics: Adult; Aged; Antibodies, Monoclonal; Basiliximab; BK Virus; Calcineurin Inhibitors; Everolimus; Female; Germany; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Induction Chemotherapy; Kidney Diseases; Kidney Transplantation; Maintenance Chemotherapy; Male; Middle Aged; Mycophenolic Acid; Polyomavirus Infections; Recombinant Fusion Proteins; Retrospective Studies; Risk Factors; Transplantation, Homologous; Tumor Virus Infections; Viremia

Regular screening for the BK virus (BKV) is recommended for early intervention in renal transplant patients. Identification of predictors for the development of BK viremia would improve their monitoring. We performed a retrospective study investigating whether the lymphocyte count may be a predictor of BKV development in renal transplant patients.. We retrospectively analyzed 268 renal transplant patients who were followed in our clinic from January 2011 to August 2014. The viral loads of BKV in blood detected by quantitative real-time polymerase chain reaction test were performed according to relevant guidelines. We also retrospectively monitored lymphocyte count, creatinine, immunosuppressive drug doses, and tacrolimus/cyclosporine/mTor inhibitors levels during the same time as BKV screening. Demographic and other clinical data were extracted from patients' files. The calculation of correlation coefficients and receiver operating characteristics (ROC) curve analysis were performed.. Overall, 16 patients (5.9%) who experienced BKV-DNA positivity were included the study. Mean age of patients was 38.2 ± 12.8 years. All patients received steroid and calcineurin inhibitors (CNIs). Mycophenolate mofetil/mycophenolic acid (MMF/MPA) was administered to 14 patients. BKV-DNA was found in 64 of the 88 (72.7%) plasma samples. The lymphocyte count on the first day of positive BKV-DNA test was significantly lower than in those with negative BKV-DNA results (1700/μl vs 2400/μl, respectively; P = .009). Its AUC of the ROC curve was 0.77 (P = .012). The optimal cutoff point for lymphocyte count was 1900/μl, and sensitivity and specificity for predict BKV positivity were 75% and 78.57%, respectively. We also found that lymphocyte count negatively correlated with the first detectable BKV titers (r = -0.438; P = .015). However, there is no relation between CNI/mTOR inhibitor levels, MMF/MPA doses, lymphocyte count, and all BKV-titers.. Decreased lymphocyte count may be a predictor for preceding BKV viremia. Clinicians should be more careful in terms of the decreased lymphocyte count in case of BKV replication in renal transplant patients.

Topics: Adult; Aged; BK Virus; Calcineurin Inhibitors; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphocyte Count; Male; Middle Aged; Mycophenolic Acid; Polyomavirus Infections; Real-Time Polymerase Chain Reaction; Retrospective Studies; Steroids; Tacrolimus; Tumor Virus Infections; Viral Load; Viremia; Virus Replication; Young Adult

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.

Topics: Arthritis, Rheumatoid; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Middle Aged; Mycophenolic Acid; Opportunistic Infections; Polyomavirus; Polyomavirus Infections; Pulmonary Fibrosis; Tacrolimus

To analyze the risk factors affecting BK virus associated nephropathy (BKVAN) after kidney transplantation.. Three screening methods for BKVAN including quantitative PCR assay for BK virus (BKV) DNA load in urine and plasma and quantitative assay of urine cytology concurrently with renal transplant biopsies for the evaluation of 615 patients from January 2006 to December 2014 were used. The renal allograft biopsy specimens were analyzed by routine histologic examination, immunohistochemistry and classified into three categories of BKVAN. Potential variables were analyzed by Logistic regression model multivariate analysis to assess and rank BKVAN related risk factors.. The positive rate of urine decoy cell , BKV viruria and viremia in 615 renal recipients were 13.7% (84/615), 29.3% (180/615), and 8.8% (54/615), respectively. BKVAN were diagnosed in 49 recipients. The incidence and the median level of the number of the decoy cell, BK viral load in urine and plasma were higher in the BKVAN group than those in non-BKVAN group (all P<0.05). Tacrolimus (Tac) combined with mycophenolic acid (MPA) protocol (OR=12.4, P=0.001) and severe pneumonia post-transplant (OR=3.7, P=0.001) were the independent risk factors impacting on BKVAN in renal recipients.. The renal recipients with high level of BKV replication, whose immunosuppressant protocol include Tac and MPA, should be suspected the diagnosis of BKVAN.

Topics: Biopsy; BK Virus; DNA, Viral; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Polyomavirus Infections; Real-Time Polymerase Chain Reaction; Risk Factors; Tacrolimus; Transplant Recipients; Transplantation, Homologous; Viral Load; Viremia

BK viremia and polyomavirus-associated nephropathy (PVN) represent a significant problem after kidney transplantation. Both are associated with intensified immunosuppression, but other risk factors and the impact of a screening program on outcome are incompletely understood.. Here, we report on the short- and long-term outcome of a cohort of patients, who were transplanted in 2006/2007 and included in a newly introduced systematic 3-monthly screening for BK viremia at the University Hospital Zurich. In patients testing positive for BK viremia, screening frequency was intensified and immunosuppression reduced. Patients with suspected PVN underwent transplant biopsy.. Among 152 included patients, 49 (32%) tested positive for BK viremia, but only 8 developed biopsy-proven PVN. BK viremia had a significant impact on estimated glomerular filtration rate and proteinuria in the first 2 years. Acute rejection episodes and the number of human leukocyte antigen (HLA) mismatches were the strongest independent predictors of BK viremia in a multiple logistic model. In contrast, no particular immunosuppressive agent or regimen was associated with enhanced risk.. Taken together, systematic BK viremia screening led to detection of a high percentage of viremic patients. With adjustment of immunosuppression, an excellent outcome was achieved. The independent association of HLA mismatches with BK viremia suggests impaired polyomavirus immunosurveillance in highly mismatched allografts.

Topics: Adult; Aged; Allografts; Antibodies, Monoclonal; Azathioprine; Basiliximab; BK Virus; Cohort Studies; Cyclosporine; Female; Glomerular Filtration Rate; Graft Rejection; Histocompatibility; HLA Antigens; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Logistic Models; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Polyomavirus Infections; Proteinuria; Pyrroles; Quinazolines; Recombinant Fusion Proteins; Tacrolimus; Tumor Virus Infections; Viremia

The clinical epidemiology of BK virus (BKV) disease after allogeneic hematopoietic stem cell transplantation (HSCT) is not well defined. We evaluated 491 patients transplanted from January 2010 to December 2011 at a single transplant center to assess incidence, severity, and risk factors for BKV disease after HSCT. BKV disease was defined as BKV detection in urine by PCR testing in association with genitourinary symptoms without other concurrent genitourinary conditions. BKV disease occurred in 78 patients (15.9%), for an incidence rate of .47/1000 patient-days (95% confidence interval [CI], .37 to .59); BKV disease was considered severe in 27 patients (5.5%). In multivariate Cox modeling, time-dependent acute graft-versus-host disease (aGVHD) grades II to IV (adjusted hazard ratio [aHR] 4.25; 95% CI, 2.51 to 7.21), cord blood HSCT (aHR 2.28; 95% CI, 1.01 to 5.15), post-transplant mycophenolate use (aHR 3.31; 95% CI, 1.83 to 5.99), and high-dose cyclophosphamide conditioning (aHR 2.34, 95% CI 1.45 to 3.77) were significant predictors of BKV disease. Time-dependent aGVHD grades III to IV (aHR 10.5; 95% CI, 4.44 to 25.0) and cord blood HSCT (aHR 5.40; 95% CI, 1.94 to 15.0) were independent risk factors for severe BKV disease. BKV disease is common and is associated with significant and prolonged morbidity after HSCT. Prospective studies are needed to better define the morbidity of post-HSCT BKV disease and inform the design of prophylaxis and treatment trials.

Topics: Adult; Aged; BK Virus; Chronic Disease; Cord Blood Stem Cell Transplantation; Cyclophosphamide; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Mycophenolic Acid; Myeloablative Agonists; Polyomavirus Infections; Prospective Studies; Severity of Illness Index; Transplantation Conditioning; Transplantation, Homologous; Tumor Virus Infections

We report the successful management of BK virus nephropathy (BKVN) using therapeutic drug monitoring (TDM) of mycophenolic acid (MPA). A 40-year-old woman was admitted for a protocol biopsy 3 months following primary kidney transplantation. Histological features were distributed in mainly two sections: the corticomedullary junction and cortical area. In the former, massive interstitial mononuclear cell infiltration and mild to moderate tubulitis with nuclear inclusion bodies were found. SV40 staining was positive in the injured tubules. These findings were compatible with BKVN. In the latter, focal interstitial inflammation and severe tubulitis without cytopathic changes were identified outside of SV40-positive areas. Based on the histological findings, we diagnosed BKVN and we also suspected of the complication with acute T-cell-mediated rejection. We started steroid pulse therapy and reduced the dosage of immunosuppressive therapy under careful monitoring, using not only a trough level of tacrolimus but also a 12-h area under the curve (AUC0-12 ) of MPA. After the treatment, the patient maintained kidney function. This case report demonstrates the usefulness of MPA AUC0-12 for more accurate adjustment of immunosuppressive therapy and the difficulty of pathological differentiation of BKVN and acute cellular rejection.

Topics: Adult; Antibiotics, Antineoplastic; BK Virus; Drug Monitoring; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Nephritis; Polyomavirus Infections; Steroids; Tumor Virus Infections

BK virus nephropathy and cellular rejection are common causes of allograft dysfunction in renal transplant recipients. The two can be difficult to distinguish on allograft biopsy and can be present simultaneously. Management of the patient with coexistent BK infection and rejection is complicated by the conflicting ideals of decreasing immunosuppression to treat the former and increasing immunosuppression to treat the latter. The authors present the case of a 57-year-old renal transplant recipient who underwent allograft biopsy 8 weeks post-transplant for evaluation of increased serum creatinine in the setting of BK viremia (BKV). Biopsy revealed Banff classification 1b acute cellular rejection, with insufficient evidence to diagnose BK virus-associated nephropathy. The patient was administered intravenous immune globulin (IVIG), with no other changes in immunosuppressive therapy. Plasma and urine BK increased exponentially following IVIG administration, and allograft function further deteriorated. Repeat biopsy showed overt BK viral nephropathy, and BKV and creatinine decreased only after reduction in immunosuppression and initiation of leflunomide. Although case series have suggested a potential role for IVIG in the setting of BK infection, further study is needed to define the safety and efficacy of this approach.

Topics: BK Virus; Fatal Outcome; Female; Graft Rejection; Humans; Immunity, Cellular; Immunoglobulins, Intravenous; Immunologic Factors; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Polyomavirus Infections; Renal Insufficiency; Tacrolimus; Tumor Virus Infections; Viremia

There is continued and significant debate regarding the salient etiologies associated with graft loss and racial disparities in kidney transplant recipients.. This was a longitudinal cohort study of all adult kidney transplant recipients, comparing patients with early graft loss (<5 years) to those with graft longevity (surviving graft with at least 5 years of follow-up) across racial cohorts [African-American (AA) and non-AA] to discern risk factors.. 524 patients were included, 55% AA, 151 with early graft loss (29%) and 373 with graft longevity (71%). Consistent within both races, early graft loss was significantly associated with disability income [adjusted odds ratio (AOR) 2.2, 95% CI 1.1-4.5], Kidney Donor Risk Index (AOR 3.2, 1.4-7.5), rehospitalization (AOR 2.1, 1.0-4.4) and acute rejection (AOR 4.4, 1.7-11.6). Unique risk factors in AAs included Medicare-only insurance (AOR 8.0, 2.3-28) and BK infection (AOR 5.6, 1.3-25). Unique protective factors in AAs included cardiovascular risk factor control: AAs with a mean systolic blood pressure <150 mm Hg had 80% lower risk of early graft loss (AOR 0.2, 0.1-0.7), while low-density lipoprotein <100 mg/dl (AOR 0.4, 0.2-0.8), triglycerides <150 mg/dl (AOR 0.4, 0.2-1.0) and hemoglobin A1C <7% (AOR 0.2, 0.1-0.6) were also protective against early graft loss in AA, but not in non-AA recipients.. AA recipients have a number of unique risk factors for early graft loss, suggesting that controlling cardiovascular comorbidities may be an important mechanism to reduce racial disparities in kidney transplantation.

Topics: Adult; Aged; BK Virus; Black or African American; Cardiovascular Diseases; Cohort Studies; Dyslipidemias; Female; Graft Rejection; Graft Survival; Health Status Disparities; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Longitudinal Studies; Male; Medicare; Middle Aged; Mycophenolic Acid; Odds Ratio; Polyomavirus Infections; Prednisone; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors; United States

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.

Topics: Adult; Aged; Biopsy; BK Virus; Female; Humans; Immunosuppression Therapy; Kidney; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Polyomavirus Infections; Postoperative Complications; Prospective Studies; Tacrolimus; Tumor Virus Infections; Viral Load

Overimmunosuppression is a widely recognized risk factor for BK virus (BKV) infection, particularly with the combination of tacrolimus, mycophenolate mofetil (MMF), and steroids. Nevertheless, the exact impact of exposure to tacrolimus and MMF is not well understood.. We examined 240 kidney recipients between 2006 and 2008. BKV was monitored every 2 months in the urine or blood. A kidney biopsy was performed when viremia exceeded 10 copies/mL.. Ninety-five (40%) patients had sustained viruria, 48 (20%) sustained viremia, and 17 (7%) biopsy-proven polyomavirus-associated nephropathy. The mean time-to-occurrence was 7.6, 7.9, and 9.7 months for viruria, viremia, and polyomavirus-associated nephropathy. Risk factors associated with BKV infection in univariate analyses were retransplantation, panel-reactive antibody more than 0%, cytomegalovirus D+/R-, cold ischemia time, delayed graft function, induction with antithymocyte globulins, acute rejection before month 3 (M3), tacrolimus trough levels more than 10 ng/mL, and M3 AUC0-12 hr more than 50 hr mg/L. Multivariate analyses showed that cytomegalovirus D+/R- (adjusted hazard ratio [AHR], 2.03; P=0.05), acute rejection (AHR, 5.4; P<0.001), and mycophenolic acid AUC0-12 hr more than 50 hr mg/L (AHR, 3.6; P=0.001) were risk factors for BKV.. This study identified a link between a state of increased immunosuppression and BKV infection, especially in patients with higher MMF exposure and elevated tacrolimus trough levels at M3.

Topics: Adolescent; Adult; Aged; Area Under Curve; Biopsy; BK Virus; Drug Monitoring; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polyomavirus Infections; Renal Insufficiency; Risk Factors; Steroids; Tacrolimus; Viremia; Young Adult

We have used low doses of mizoribine (MZ) or mycophenolate mofetil (MMF) as induction and maintenance immunosuppressants, but since 2009 have employed a high dose of MZ. We reviewed the efficacy and side effects of MZ compared with MMF. It is difficult to compare graft survivals between these periods because of different patient demographics, though the high dose of MZ cohort showed no significant difference from MMF. High doses of MZ serum to prevent acute rejection episodes as the induction and maintenance therapy. MZ controlled with blood concentrations showed less side effects, suggesting that high MZ doses could be safely used for an induction and maintenance antimetabolite.

Topics: Adolescent; Adult; BK Virus; Child; Cytomegalovirus Infections; Female; Graft Rejection; Graft Survival; Herpes Zoster; Humans; Immunosuppressive Agents; Japan; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polyomavirus Infections; Retrospective Studies; Ribonucleosides; Treatment Outcome; Young Adult

BK virus is an infection in kidney transplantation patients jeopardizing graft survival. Unfortunately, there is no consensus on treatment of BK viremia and nephropathy. Leflunomide has been studied for the treatment of BK viremia and nephropathy, but there are limited data on the utility of leflunomide therapeutic drug monitoring. This study aimed to determine if a pharmacodynamic relationship exists between BK viral load reduction and leflunomide metabolite, A77 1726, serum concentrations.. This study was a retrospective, single-center, longitudinal analysis of patients identified with BK viremia with or without nephropathy. Patients were grouped according to whether they received leflunomide. All BK viral PCR and A77 1726 concentrations were analyzed to determine pharmacodynamics, and were correlated with clinical outcomes.. Of 76 patients identified, 52 received leflunomide therapy and 24 did not. Patients who received leflunomide were further analyzed according to A77 1726 concentrations and BK clearance; there was no difference in BK clearance. There was a lack of correlation between A77 1726 concentrations and log change in BK viral PCR concentration. Multivariate analysis demonstrated that mycophenolate mofetil discontinuation, BK viremia without nephropathy, and mean BK viral load were significantly associated with BK viral clearance; leflunomide use lacked this association.. Pharmacodynamic analysis revealed no association between A77 1726 concentrations and BK viral PCR reductions. Multivariate analysis demonstrated that leflunomide therapy was not associated with BK viral clearance. Randomized studies are needed to determine the utility of leflunomide for BK viremia and nephropathy.

Topics: Adult; Aniline Compounds; Antiviral Agents; Biotransformation; BK Virus; Chi-Square Distribution; Crotonates; Drug Monitoring; Female; Humans; Hydroxybutyrates; Immunosuppressive Agents; Isoxazoles; Kidney Transplantation; Leflunomide; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Nitriles; Polymerase Chain Reaction; Polyomavirus Infections; Proportional Hazards Models; Retrospective Studies; South Carolina; Toluidines; Treatment Outcome; Tumor Virus Infections; Viral Load

BK virus (BKV)-induced viraemia after renal transplantation can be associated with severe impairment of graft function. This study evaluated possible risk factors for BKV replication and examined the outcomes following various currently used treatment approaches.. Fifty-seven renal transplant recipients with BKV viraemia were retrospectively compared with 71 BKV-negative recipients to identify risk factors for BKV viraemia. Furthermore, outcome and graft function in 14 patients with BKV replication, in whom mycophenolate mofetil (MMF) was discontinued with a dose reduction of the remaining immunosuppressants, were compared with 32 patients in whom both MMF and the additional immunosuppressants were reduced.. Patients with BKV viraemia received MMF (p < 0.01) and triple immunosuppression (p < 0.01) significantly more often, and displayed tacrolimus (p = 0.034) at higher blood concentrations (p = 0.002), a lower lymphocyte count (p = 0.006) and a longer warm ischaemic time (p = 0.019), and were more often male (p = 0.026). Patients in whom MMF was stopped had a higher chance of clearance of BKV viraemia (p = 0.022), which was achieved more rapidly (p = 0.048). Graft function improved during treatment and no graft losses occurred, compared with eight graft losses in the MMF-treated group (p = 0.04).. MMF and tacrolimus could promote BKV viraemia after renal transplantation. Discontinuation of MMF together with a reduction of calcineurin inhibitors and glucocorticoids could be an option to reduce BKV replication after renal transplantation.

Topics: Adult; Anti-Inflammatory Agents; BK Virus; Confidence Intervals; Cyclosporine; Drug Therapy, Combination; Female; Graft Survival; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Transplantation; Lymphocyte Count; Male; Middle Aged; Mycophenolic Acid; Odds Ratio; Polyomavirus Infections; Prednisolone; Retrospective Studies; Risk Factors; Tacrolimus; Tumor Virus Infections; Viral Load; Virus Replication; Warm Ischemia

BK viremia can lead to nephritis, which can progress to irreversible kidney transplant failure. Our prospective study provides management and outcome of BK viremia in renal transplant recipients.. Two hundred forty de novo kidney-only recipients were enrolled from July 2007 to July 2010 and followed for 1 year. Standard immunosuppression with Thymoglobulin/interleukin 2 receptor blocker and mycophenolate mofetil/tacrolimus (Tac)/prednisone was employed. Quantitative BK virus (BKV) DNA surveillance in plasma/urine was performed at 1, 3, 6, 12, and 24 months after transplantation. Patients with significant viremia (defined as ≥10,000 viral copies/mL) underwent renal biopsy and treated with 30% to 50% reduction in doses of both mycophenolate mofetil and Tac without antiviral therapy. The target 12-hr Tac trough levels were lowered to 4 to 6 ng/mL in the significant viremia group, whereas the target levels remained unchanged at 5 to 8 ng/mL for all other groups.. Sixty-five patients (27%) developed BK viremia; 28 (12%) of whom had significant viremia. A total of five (21%) of the 23 (of 28) patients who underwent biopsy presented with subclinical BKV nephritis. The mean plasma BKV DNA declined by 98% (range, 76%-100%) at 1 year after peak viremia. Acute cellular rejection seen in four (14%) of 28 patients, responded to bolus steroids. There was no decline in estimated glomerular filtration rate over time from 1 month after transplantation to 1 year after peak viremia (P=0.57).. Reduction in immunosuppression alone resulted in the successful resolution of viremia with preservation of renal function and prevention of clinical BKV nephritis and graft loss.

Topics: Adult; Aged; Biopsy; BK Virus; Female; Humans; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Nephritis; Polyomavirus Infections; Postoperative Complications; Prospective Studies; Tacrolimus; Treatment Outcome; Tumor Virus Infections; Viral Load; Viremia

The 2008-released FDA safety report described a potential association between use of MMF and progressive multifocal leukoencephalopathy. We here report the case of an 11-yr-old kidney transplanted boy suffering from PML who showed rapid improvement parallel to withdrawal of MMF. This case contributes to the increasing knowledge on side effects of MMF treatment in children.

Topics: Child; Follow-Up Studies; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Leukoencephalopathy, Progressive Multifocal; Male; Mycophenolic Acid; Polyomavirus; Polyomavirus Infections; Risk Assessment; Transplantation Immunology; Tumor Virus Infections; Withholding Treatment

BK virus (BKV) is increasingly found as an important cause of allograft nephropathy. Nephrotic syndrome is not a usual manifestation of BKV nephropathy. Here, we report a 12-year-old boy, a case of end-stage renal disease due to nephronophthisis, who got the kidney transplanted from a 16-year-old cadaver, and after 18 months of uneventful transplantation on triple immunosuppressive therapy (mycophenolate mofetil (MMF), cyclosporin and prednisolone), presented with nephrotic feature (edema, heavy proteinuria, hypoalbuminemia and hyperlipidemia). Kidney biopsy was in favor of BKV infection and eventually ended in graft failure.

Topics: Adolescent; Biopsy; BK Virus; Child; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Nephrotic Syndrome; Polyomavirus Infections; Prednisolone; Time Factors; Transplantation, Homologous; Treatment Outcome; Tumor Virus Infections

The aim was to report our experience of BK viremia surveillance after kidney transplant during a period of change from cyclosporine (CyA)-to lower-dose tacrolimus (Tac)-based primary immunosuppression regimens.. In a prospective single-center observational cohort study, 68 consecutive patients received renal transplant during the period when we used a CyA-based primary immunosuppression regimen and 66 after we changed to a lower-dose Tac-based regimen. Testing for BK viremia by quantitative polymerase chain reaction assay was performed at least monthly for a minimum of 1 year.. Thirty-nine (29.1%) patients developed BK viremia and 2 (1.5%) developed BK nephropathy. The actuarial time to BK viremia was shorter in patients receiving CyA/mycophenolate mofetil (MMF)/prednisolone (Pred) compared with Tac/MMF/Pred (P=0.04) and primary immunosuppression with CyA/MMF/Pred was the only independent predictor of BK viremia (hazard ratio 1.95; P=0.047). Comparing patients who experienced BK viremia and those who did not, there was no difference in incidence of acute rejection (20.5% vs. 25.3%; P=0.56) or estimated glomerular filtration rate at 12 months (48.8 vs. 49.9 mL/min/1.73 m(2)), but the incidence of ureteric stenosis was higher (10.3% vs. 1.1%; P=0.01).. Our data demonstrate a lower incidence of BK viremia in patients on lower-dose Tac compared with CyA-based primary immunosuppression in contrast to previous studies, and provide further support for the association between BK virus and ureteric complications.

Topics: BK Virus; Cyclosporine; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Polyomavirus Infections; Prednisolone; Tacrolimus; Time Factors; Tumor Virus Infections; Viremia

Nowadays, better immunosuppressors have decreased the rates of acute rejection in kidney transplantation, but have also led to the emergence of BKV-associated nephropathy (BKVAN). Therefore, we prospectively investigated BKV load in plasma and urine samples in a cohort of kidney transplants, receiving basiliximab combined with a mycophenolate mofetil-based triple immunotherapy, to evaluate the difference between BKV replication during the first 3 months post-transplantation, characterized by the non-depleting action of basiliximab, versus the second 3 months, in which the maintenance therapy acts alone. We also performed sequencing analysis to assess whether a particular BKV subtype/subgroup or transcriptional control region (TCR) variants were present.. We monitored BK viruria and viremia by quantitative polymerase chain reaction (Q-PCR) at 12 hours (Tx), 1 (T1), 3 (T2) and 6 (T3) months post-transplantation among 60 kidney transplant patients. Sequencing analysis was performed by nested-PCR with specific primers for TCR and VP1 regions. Data were statistically analyzed using χ² test and Student's t-test.. BKV was detected at Tx in 4/60 urine and in 16/60 plasma, with median viral loads of 3.70 log GEq/mL and 3.79 log GEq/mL, respectively, followed by a significant increase of both BKV-positive transplants (32/60) and median values of viruria (5.78 log GEq/mL) and viremia (4.52 log GEq/mL) at T2. Conversely, a significantly decrease of patients with viruria and viremia (17/60) was observed at T3, together with a reduction of the median urinary and plasma viral loads (4.09 log GEq/mL and 4.00 log GEq/mL, respectively). BKV TCR sequence analysis always showed the presence of archetypal sequences, with a few single-nucleotide substitutions and one nucleotide insertion that, interestingly, were all representative of the particular subtypes/subgroups we identified by VP1 sequencing analysis: I/b-2 and IV/c-2.. Our results confirm previous studies indicating that BKV replication may occur during the early hours after kidney transplantation, reaches the highest incidence in the third post-transplantation month and then decreases within the sixth month, maybe due to induction therapy. Moreover, it might become clinically useful whether specific BKV subtypes or rearrangements could be linked to a particular disease state in order to detect them before BKVAN onset.

Topics: Adult; Antibodies, Monoclonal; Base Sequence; Basiliximab; BK Virus; Cohort Studies; DNA, Viral; Follow-Up Studies; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Italy; Kidney; Kidney Transplantation; Molecular Sequence Data; Mutagenesis; Mycophenolic Acid; Polyomavirus Infections; Real-Time Polymerase Chain Reaction; Recombinant Fusion Proteins; Sequence Analysis, DNA; Viral Load; Virus Replication

BK polyomavirus (BKV) infection and BKV-associated nephropathy (BKVAN) are among the most important problems in renal transplantation. We aimed to determine the incidence of BK viruria, viremia, and BKVAN in renal transplant recipients in the northeastern part of Poland.. Urine and blood samples from 126 cadaveric renal transplant recipients were analyzed for BK viruria and viremia using quantitative real-time polymerase chain reaction and the patients were followed prospectively. The diagnosis of BKVAN was established on the allograft biopsy.. Based on the BKV DNA analysis, the patients were divided into three groups: group 1 (n=89; 70.6%) without viruria or viremia, group 2 (n=24; 19.1%) with isolated viruria, and group 3 (n=13; 10.3%) with both viruria and viremia. The presence of BK viremia negatively correlated with time after the transplantation. BK viruria was associated with mycophenolate mofetil daily dose. In group 3 there were four patients (3.2%) with high viremia (>10(4) genome equivalents [gEq]/mL) and viruria (>10(7) gEq/mL) loads. Only one patient from this group developed clinical symptoms and had BKVAN in allograft biopsy. In all four cases, the maintenance immunosuppression therapy was based on tacrolimus and steroids.. Prevalence of BKV infection in renal transplant recipients in the northeastern part of Poland is similar to that reported by studies from other countries. We confirm that BK viremia could be predicted by the presence of intense viruria. Time after transplantation and the type of immunosuppression strategy are the most important predictors of BK viremia and viruria in patients after renal transplantation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; BK Virus; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Poland; Polyomavirus Infections; Risk Factors; Tumor Virus Infections; Viremia; Virus Replication; Young Adult

Topics: Area Under Curve; BK Virus; Case-Control Studies; Humans; Immunosuppressive Agents; Mycophenolic Acid; Polyomavirus Infections; Risk Factors; Tacrolimus; Virus Replication

Polyomavirus-associated nephropathy (PyVAN) is rare in nonrenal solid organ transplantation and only limited information is available from single cases. We describe a 67-year-old female presenting with hypertension and progressive kidney failure due to PyVAN 60 months after lung transplantation. Plasma BK virus (BKV) loads were 4.85 log¹⁰ copies/mL at diagnosis and cleared slowly over 14 months after switching from tacrolimus, mycophenolate and prednisone to low-dose tacrolimus, sirolimus and leflunomide, the latter being discontinued for anemia and diarrhea. BKV- and JC virus-specific immunoglobulins were detectable prior to transplantation. Only BKV-specific IgG and IgM increased during follow-up. BKV-specific T cells were detectable in blood following in vitro expansion, but cleared with reincreased sirolimus, yet BKV viremia remained undetectable. We identified eight other cases of PyVAN in nonrenal solid organ transplantation including lung (n = 1), heart (n = 6) and pancreas (n = 1). Overall, diagnosis was later than commonly seen in kidney transplants (median 18 months, interquartile range 10-29). Seven patients were male, five received triple immunosuppression consisting of tacrolimus, mycophenolate, prednisone. Immunosuppression was reduced in four cases and cidofovir and/or leflunomide administered in five and two cases, respectively. Renal function deteriorated in five requiring hemodialysis in four. We discuss mTOR inhibitors versus cidofovir and leflunomide as potential PyVAN rescue therapy.

Topics: Adult; Aged; Cidofovir; Cytosine; Female; Humans; Isoxazoles; Kidney Diseases; Leflunomide; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Organophosphonates; Polyomavirus Infections; Prednisone; Renal Insufficiency; Tacrolimus; TOR Serine-Threonine Kinases

Polyoma BK virus nephropathy is a serious complication after renal transplantation and is associated with a high rate of allograft failure. Progressive infection with BK virus in immunocompromised renal transplant recipients occurs in detectable stages: Viruria, viremia, then nephropathy.. In January, 2006, we initiated a plasma screening policy for all new transplant recipients, with monthly blood testing for BK virus by polymerase chain reaction (PCR). Between January 1, 2006, and February 28, 2007, 66 renal transplants were performed at our center. The 11 patients with a positive plasma BK PCR test underwent prompt reduction in baseline immunotherapy consisting of a 50% daily dose reduction (n = 6) or complete discontinuation of therapy with mycophenolate mofetil (n = 5).. After reduction or discontinuation of mycophenolate mofetil, 10 patients became negative for BK virus in the plasma within 6 months. Progression to BK nephropathy has not occurred, and renal transplant dysfunction secondary to acute cellular rejection developed in only 1 patient (9%). One year post-transplant, the mean serum creatinine values for these 11 patients remained stable at 1.5 mg/dL.. Monthly plasma screening for BK virus by PCR together with immunosuppressive regimen reduction prevents BK nephropathy. In addition, this intensive screening protocol is associated with a low rate of acute rejection and excellent preservation of renal function.

Topics: BK Virus; Case-Control Studies; DNA, Viral; Drug Administration Schedule; Female; Graft Survival; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polymerase Chain Reaction; Polyomavirus Infections; Tumor Virus Infections; Viremia

In kidney-transplant recipients, leflunomide has been shown to be efficient for treating polyomavirus BK virus-associated-nephropathy (PVAN). However, it is unknown whether the beneficial effect of leflunomide is related to it having a lower immunosuppressive effect than mycophenolate mofetil (MMF), or to its anti-viral activity. The aim of this study was to assess i) T-cell functions before and after conversion from MMF to leflunomide in kidney-transplant patients with PVAN, and ii) effects of leflunomide on PVAN outcome.. Twelve patients were enrolled in this study. At PVAN diagnosis, MMF was replaced by leflunomide. Other immunosuppressive drug doses and levels were maintained unchanged. T-cell functions, i.e., intralymphocyte cytokine expression (IL-2 and TNF-alpha), T-cell activation [i.e., transferrin receptor (CD71) and interleukin (IL)-2 alpha-chain (CD25) expression], and T-cell proliferation were measured using a flow-cytometry whole-blood assay before and at one month after conversion.. Despite a slight decrease in tacrolimus trough levels, no significant change in T-cell-function biomarkers was observed after conversion. After a follow-up of 6 (4-30) months, five patients were cleared of the virus, and decreased viral load was observed in four patients. Only one patient suffered a graft loss. No difference in immunological parameters was observed between patients who were cleared or not of BKV.. Results of this pilot study suggest that the potential benefits of leflunomide to treat PVAN in kidney-transplant patients is not related to reduced immunosuppression induced by replacing MMF by leflunomide. Virological studies are required to determine the anti-BKV effect of leflunomide.

Topics: Adult; Aged; Antigens, CD; BK Virus; Cell Proliferation; Disease Progression; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Isoxazoles; Kidney; Kidney Transplantation; Leflunomide; Male; Middle Aged; Mycophenolic Acid; Nephritis; Polyomavirus Infections; Receptors, Transferrin; T-Lymphocytes; Treatment Outcome; Tumor Necrosis Factor-alpha

The specific role of different immunosuppressive agents as risk factors for BK virus nephropathy (BKN) has not been well studied.. In this case-control study, we examined the association of tacrolimus (TAC), mycophenolate mofetil (MMF), and prednisone with BKN in renal allograft recipients transplanted between 1997 and 2004 at our center who underwent biopsies for allograft dysfunction. Drug levels or doses were recorded during the 3 months before the index biopsy. Random effects logistic modeling was used for data analysis.. There were 33 cases with BKN, biopsied at 16.4+/-2.8 months and 66 matched controls with biopsies at 21.5+/-2.1 months posttransplant (P=0.16). After adjusting for sex, race, retransplant status, diabetes, donor source, and induction agent, TAC blood level was associated with increased risk of BKN (odds ratio [OR] 1.3, 95% confidence interval [CI] 1.02-1.7, P=0.03), whereas MMF dose was not (OR 1.0, 95% CI 0.99-1.0, P=0.2). Moreover, prednisone dose was also found to be a significant risk factor for BKN (OR 1.22, 95% CI 1.04-1.4, P=0.02).. The results of this study show that BKN is associated with TAC level and prednisone dose and not with MMF dose. This suggests that reducing TAC and prednisone dose and maintaining MMF may be a more appropriate initial approach for the treatment of BKN. Further studies are needed to compare the efficacy and safety of this approach with the currently recommended one.

Topics: Biopsy; BK Virus; Case-Control Studies; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Logistic Models; Male; Middle Aged; Mycophenolic Acid; Odds Ratio; Polyomavirus Infections; Prednisone; Risk Assessment; Risk Factors; Tacrolimus; Time Factors; Transplantation, Homologous; Virus Activation

Reducing immunosuppression is the treatment of choice for polyomavirus-associated nephropathy in kidney transplant (KT) patients, but strategies and targets are uncertain.. Using interferon-gamma ELISpot assays, we investigated immunosuppressive drug levels and polyomavirus BK (BKV) large T-antigen-specific T-cell responses in KT patients in vivo and in healthy donors after titrating immunosuppression in vitro.. In KT patients, BKV-specific T-cell responses were inversely correlated with tacrolimus trough levels (R=0.28, P<0.002), but not with mycophenolate levels, prednisone, or overall immunosuppressive dosing. In vitro tacrolimus concentrations above 6 ng/mL inhibited BKV- and cytomegalovirus-specific T-cells more than 50%, whereas less than 30% inhibition was observed below 3 ng/mL. Inhibition by cyclosporine A was more than 50% at concentrations of 1920 ng/mL and less than 30% below 960 ng/mL, corresponding to clinical C0 trough levels of 200 and 100 ng/mL, respectively. However, mycophenolate up to 8 microg/mL, leflunomide 50 microg/mL, or sirolimus concentrations 64 ng/mL did not inhibit BKV-specific interferon-gamma production, but antigen-dependent T-cell expansion.. Calcineurin-inhibitor concentrations are critical for BKV-specific T-cell activation. Reducing calcineurin inhibitors should be considered as first step, whereas conversion to mTOR inhibitors may be an attractive alternative or second step that should be validated in clinical BKV intervention trials.

Topics: Adult; Aged; BK Virus; Cyclosporine; Female; Humans; Immunosuppressive Agents; Interferon-gamma; Isoxazoles; Kidney Transplantation; Leflunomide; Middle Aged; Mycophenolic Acid; Polyomavirus Infections; Reference Values; T-Lymphocytes; Tacrolimus

It is known that administration of mycophenolate mofetile (MMF) is associated with BK virus (BKV) nephropathy in renal transplant recipients. To determine any inhibitory effect of mizoribine for BKV, seven patients with positive BKV in their urine who took MMF as immunosuppressive therapy were evaluated after MMF was changed to mizoribine. Baseline BKV DNA in urine, which ranged from 2.2 x 10(2) to 5.5 x 10(6) copies per milliliter, decreased in all cases (mean = 1.9 x 10(-1) times; median 2.8 x 10(-3) times). Four cases turned negative within 6 months and one within 12 months. No acute rejection or deterioration of graft function occurred during the administration of mizoribine. An inhibitory effect of mizoribine on BKV was suggested.

Topics: Adult; BK Virus; DNA, Viral; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Polyomavirus Infections; Ribonucleosides

Treatment of BK virus (BKV) infection in renal transplant recipients remains controversial. This retrospective analysis evaluated efficacy and safety of reducing immunosuppression without antiviral therapy.. This single center analysis included 24 patients diagnosed with BK viremia between September 2001 and December 2003. Sixteen patients (66%) presented with BKV nephritis and eight patients (34%) presented with viremia without evidence of nephritis on renal biopsy.. At time of diagnosis, mean plasma BKV DNA (copies/mL) was 460,409 (range 10,205-1,920,691). Mean doses reduction of mycophenolate mofetil and tacrolimus were 44% and 41%, respectively, from time of diagnosis of BKV infection to complete resolution of viremia. A decline in BK viral load was noticed within 15 to 30 days, with successful elimination of viremia over a mean period of 5.8 months (range, 1-9.5). Mean serum creatinine at time of diagnosis of BK viremia was 1.8 mg/dL (range, 1.2-2.8). Mean follow-up period is 30.9 months postdiagnosis. At the most recent visit, serum creatinine was 2.0 mg/dL (range, 1.0-3.6) (P=0.14). With reduction in immunosuppressive therapy, three patients (13%) developed acute cellular rejection and were treated successfully with intravenous bolus steroids. During follow-up, one patient had a relapse of BKV nephritis during pregnancy and lost her graft. After mean follow-up period of 43.5 months posttransplantation, all 24 patients are alive and 23 have a functioning graft. Seventeen patients (71%) have stable or improved graft function.. Our analysis shows that reduction in immunosuppression therapy alone results in clearance of the BK viremia with good long-term outcome.

Topics: Acute Disease; Adult; Aged; BK Virus; Dose-Response Relationship, Drug; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polyomavirus Infections; Postoperative Complications; Prednisone; Tacrolimus; Tumor Virus Infections

Polyoma virus nephropathy is recognized as an emerging clinical problem in renal transplantation; however, polyoma in native kidneys is unusual. We report a patient who developed polyoma nephropathy in his native kidneys 15 months after successful lung transplantation. His immunosuppression consisted of tacrolimus, mycophenolate mofetil, and large doses of steroids because of three rejection episodes. When the condition was recognized, cidofovir was an effective treatment (3 doses of 2-3mg/kg); however, his renal function deteriorated nonetheless. Tubulitis and interstitial cell infiltration in his native kidneys were evidence that the changes were in response to viral injury. Polyoma nephropathy of native kidneys is unusual. An earlier course of cisplatin treatment because of metastatic seminoma prior to lung transplantation may have been contributory to pre-existing renal injury. After cidofovir was begun, the polyoma viral load in serum and urine decreased substantially; however, after high-dose steroid treatment of two rejection episodes, each time a significant increase in viral load was seen. We stained biopsies of native kidneys from 30 recipients of other organs. The biopsies were done for various reasons but not because polymoma virus was suspected. We found no additional cases.

Topics: Adult; Antiviral Agents; Biopsy; BK Virus; Cidofovir; Cisplatin; Cytosine; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Lung Transplantation; Male; Mycophenolic Acid; Neoplasm Metastasis; Organophosphonates; Polyomavirus; Polyomavirus Infections; Seminoma; Steroids; Tacrolimus

In recent years an increasing number of cases with polyomavirus (PV)-nephropathy after renal transplantation were reported from several transplant centres. New, highly potent immunosuppressive drugs like tacrolimus or mycophenolate mofetil were accused as risk factors for this increase. However, data about the incidence of PV-nephropathy in correlation to different immunosuppressive therapy concepts are lacking.. All renal transplant biopsies performed at Hannover Medical School between 1999 and 2001 (n=1276) were immunohistochemically screened for the presence of PV-specific proteins. The results were correlated to the different immunosuppressive therapy protocols and patients with PV-nephropathy were compared with a matched control group.. PV-nephropathy was found in <1% of all investigated allograft biopsies (11/1276) and in approximately 1% of all patients (7/638), respectively. All patients being immunohistochemically positive for PV-specific proteins also showed the typical morphological changes of PV-nephropathy. Four out of seven patients with PV-nephropathy were under triple immunosuppression comprising tacrolimus and mycophenolate mofetil. Under this immunosuppressive therapy protocol an eight times higher incidence and a 13 times higher risk (multivariate odds ratio 12.7) of PV-nephropathy was observed in our patients compared with the control group.. PV-nephropathy is a rare but serious complication after renal transplantation. A small group of patients under intensive immunosuppression comprising tacrolimus in combination with mycophenolate mofetil has a significantly increased risk of acquiring this deleterious complication.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polyomavirus; Polyomavirus Infections; Prospective Studies; Risk Factors; Tacrolimus; Tumor Virus Infections

Topics: BK Virus; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Opportunistic Infections; Polyomavirus Infections; Tacrolimus

Polyoma virus infection in renal transplant recipients has been observed with increasing frequency in recent years. Renal allograft involvement in this condition may occur as a result of primary infection or secondary to reactivation of the latent virus. Interstitial nephritis, ureteric stenosis, rise in serum creatinine and allograft function loss have been attributed to this viral infection.. In this study we reviewed our experience with 8 patients who developed polyoma viral infection confirmed by allograft biopsy. All patients were receiving mycophenolate mofetil as part of the immunosuppression and 7 of the 8 patients were on tacrolimus. All patients have biopsy proven polyoma viral infection. The following therapeutic maneuvers were carried out following the diagnosis of polyoma viral infection: 1) stopping mycophenolate and 2) switching tacrolimus to cyclosporine or reducing the tacrolimus dose to adjust it at a lower therapeutic trough level. The clinical course and outcome of our patients were reviewed in relation to manipulation of immunosuppressive medications.. The incidence of this infection in our transplant program in the last 3 yr was 5.3%. Seventy-five percent of the patients had at least one rejection episode and 63% had more than one rejection episode. The main risk factor for the development of polyoma viral infection was related to the intensity of immunosuppression. The use of antirejection therapy after histological diagnosis of polyoma virus infection was not associated with improvement of renal function despite the histological appearance of acute rejection. Thus, the interstitial nephritis associated with polyoma viral infection appears to be an inflammatory response to the virus rather than acute rejection. Six out of the 8 patients stabilized renal function with reduction in immunosuppression.. Reduction in immunosuppression was associated with the stabilization of renal function when instituted early. However, these patients were left with a degree of allograft dysfunction and their outcome may be significantly compromised. The lack of effective antiviral therapy for polyoma virus may limit the use of newer and more potent immunosuppressive medications.

Topics: Acute Disease; Adult; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Nephritis, Interstitial; Polyomavirus Infections; Risk Factors; Tacrolimus; Tumor Virus Infections