BK virus infection in renal transplant recipients

BK virus (BKV) is increasingly being recognized as an important pathogen among renal transplant recipients. To date, only limited information is known about BKV infections in this population; definitive data regarding the epidemiology, diagnosis, treatment, and outcome of BKV infection are lacking. Therefore, further investigations are needed. This article reviews our current understanding of BKV infections among renal transplant patients.     

BK viral infection in an Australian pediatric renal transplant population

BK virus (BKV) is recognized as a significant cause of renal allograft dysfunction in adults, and there is growing awareness of its importance in the pediatric population. Eighteen pediatric renal transplant recipients and 18 age-matched controls were prospectively studied. Anti-BKV immunoglobulin G (IgG) and IgM titres were assayed in all subjects at entry to the study. Polymerase chain reaction (PCR) for BKV DNA was performed on urine and serum at entry, and prospectively tested again at 4, 8 and 12 months. Mean age +/- s.d. of transplant recipients and controls was 14.6 +/- 3.3 and 13.9 +/- 0.33 yr respectively [not significant (NS)]. Transplant patients were studied at a mean time of 5.6 +/- 4.2 yr post-transplant. 56% of transplant patients and 39% of controls were seropositive (+ve BKV IgG) (NS). Plasma BKV PCR was positive in one transplant patient (who also had positive urine PCR) and in none of the controls. The prevalence of positive urine PCR in transplant patients was greater than in controls (33% vs. 0%, p = 0.02). Positive urine BKV PCR was more commonly found in patients treated with mycophenolate than azathioprine (p = 0.04). We conclude that the prevalence of BKV seropositivity and viral activation in this Australian pediatric renal transplant population is similar to that reported in adult and pediatric populations in other countries. BK viruria was more common in children with greater immunosuppression, suggesting that this group is at higher risk of BKV induced nephropathy.     

Ureteric and urethral stenosis: a complication of BK virus infection in a pediatric renal transplant patient

Viral infections remain an Achilles heel in solid organ transplant. In recent years, incidence of BK virus infection in the kidney transplant population is on rise. BK virus is known to cause severe renal dysfunction, ureteric stenosis, and hemorrhagic cystitis in renal transplant patients. Most of the reviews and prospective studies on BKV nephropathy pertain to the adult population. Although ureteral stenosis is known to occur in BK infection, urethral stenosis is not being reported in the literature. In this report, we describe a case of BKV nephropathy in a 16-yr-old male presenting with ureteric and urethral stenosis. To our knowledge this is the first case report of its kind in a pediatric transplant population.     

BK virus-associated hemorrhagic cystitis in a pediatric lung transplant recipient

Abstract:  BKV was first postulated to be a potential pathogen in 1971 when it was isolated in the urine of a renal transplant recipient. The pathology of BKV is generally confined to the urinary tract. In renal transplant recipients, BKV has been associated with hemorrhagic cystitis, urethral stenosis, and interstitial nephritis. Reports of BKV infection in lung transplant recipients are limited to a few case reports in adult patients. A recent report revealed that up to 32% of adult lung transplant recipients may shed BKV in their urine without symptoms or renal dysfunction. To our knowledge, there are no published reports of pediatric lung transplant recipients with BKV-associated hematuria. We hereby report a case of BKV-induced hemorrhagic cystitis in a pediatric lung transplant recipient.     

Outcome of management strategies for BK virus replication in pediatric renal transplant recipients

Abstract:  Management of BKV infection is not well defined. Eighteen pediatric renal transplant patients with BKV-PCR (+) were divided into three groups; Group 1: Viruria only (6), Group 2: Viremia with stable GFR (4), Group 3: Viremia with >25% decline in GFR and BKVAN on biopsy (8). With initial BKV-PCR(+), Group 1 received no treatment; Group 2 had MMF reduced 30%; Group 3: 6/8 had CNI discontinuation, 2/8 had reduced MMF and cidofovir. BKV, GFR and histology were compared pre- and post-treatment. In Group 1 viruria decreased in all patients; GFR remained stable. Group 2 showed reduced viremia with no GFR change. Group 3 showed reduced viremia in 8/8 patients. Patients with >50% decline in GFR from baseline (6/8) showed worse histology: 2/6 lost grafts despite no BKV on follow-up biopsy. Our results show that with viruria alone no treatment is necessary; with viremia and stable GFR, reduced immunosuppression decreases viremia and maintains GFR. With viremia and reduced GFR, immunosuppression reduction with or without cidofovir decreases viremia and stabilizes GFR in most patients. Greater than 50% reduction in GFR at BKVAN diagnosis correlates with risk for graft loss. Serial monitoring of BKV viremia with early intervention may prevent BKVAN graft loss in children.     

Pretransplant IgG antibodies to polyoma BK virus in pediatric renal transplants

Bijol V, Cimic A, Viscidi RP, Hymes LC. Pretransplant IgG antibodies to polyoma BK virus in pediatric renal transplants.
Pediatr Transplantation 2010:14:224–227. © 2009 John Wiley & Sons A/S. Abstract: We retrospectively measured IgG antibody levels to BKV in pretransplant sera and compared levels in children who developed BK viremia to a control group who remained free of infection after transplantation. Sera from 45 renal transplant patients were available for analysis (BK viremia = 23, controls = 22). Serum BKV PCR levels ranged from 3400 to 6.5 million DNA copies/mL (mean ± s.d.: 978K ± 1.77 million) and were highest in patients with BK nephritis (p = 0.007). Overall, 35% of children with BK viremia were BKV‐seronegative vs. 9% of children in control group (p = 0.04), but mean antibody levels were similar between viremic and control patients (p = 0.15). However, children who developed viremia later than six months post‐transplantation had significantly lower antibody levels compared with controls (p = 0.004) and patients with early viremia (p = 0.007), and may represent de novo infection or reinfection, rather than recurrence of latent infection. Pretransplant antibody status was significantly associated with subsequent development of BK viremia. Although our findings identified possible factors for developing BK viremia, there was sufficient overlap of both seropositive status and antibody levels among viremic patients and the control group to question the clinical utility of pretransplant IgG antibodies.     

Cross-sectional study of BK virus infection in pediatric kidney transplant recipients

BKV reactivation is associated with impaired graft function in adult kidney transplant patients. The clinical impact of BKV infection in the pediatric transplant population has not yet been fully evaluated. The objective of our study was to determine the prevalence of BKV infection in consecutive pediatric kidney transplant recipients in our center. Forty consecutive unselected pediatric kidney transplant recipients were studied. Mean age at screening was 15.6 +/- 5.3 yr and samples were obtained a median of 60.5 months after transplantation (3-123). BKV-DNA was analyzed in urine and plasma by qualitative nested-PCR. A review of the literature was performed. Prevalence of viruria and viremia was 50% and 12.5%, respectively. Viremia was associated with the presence of hematuria (p = 0.02). The mean creatinine level in children without BKV replication was 1.6 mg/dL, BKV viruria was 0.9 mg/dL, and BKV viremia was 0.8 mg/dL. A literature review showed that viruria and viremia were found in 28.2% and 8.5% of cases, respectively; BKV nephropathy was found in 3.8% and graft loss in 11% of the patients with BKV nephropathy and in 0.4% of the children studied. Recipient serostatus was the most important risk factor. The rate of BKV replication and nephropathy among pediatric kidney recipients is similar to that of adults, but the incidence of graft loss is significantly lower.     

Leflunomide therapy for BK virus allograft nephropathy in pediatric and young adult kidney transplant recipients

Araya CE, Garin EH, Neiberger RE, Dharnidharka VR. Leflunomide therapy for BK virus allograft nephropathy in pediatric and young adult kidney transplant recipients.
Pediatr Transplantation 2010: 14: 145–150. © 2009 Wiley Periodicals, Inc.
Abstract:  BKVAN affects about 5% of kidney transplant recipients and may lead to graft failure. Treatment for BKVAN is challenging. Leflunomide, an immunosuppressant with antiviral activity in vitro was used successfully in some adult patients but there are no reports of its use in pediatric patients. We present our experience with three kidney transplant recipients with BKVAN who received leflunomide. Three male patients aged 9, 12, and 20 yr developed BKVAN at 9, 12, and 2 months after a kidney transplant. Immunosuppression was reduced and cidofovir was administered in all patients 2–3 wk apart. Due to inability to travel to receive cidofovir in one, lack of reduction in BK viral load in the second, and rising serum creatinine despite cidofovir in the third patient, we discontinued cidofovir and initiated leflunomide. Teriflunomide target trough levels were 30–60 μg/mL. The patients received leflunomide for 27, 26, and 24 months, respectively. BK viral load decreased below 1000 DNA copies/mL in one and was undetectable in two patients after beginning leflunomide. All patients tolerated leflunomide without side effects. Leflunomide use in a select group of patients is well tolerated and may provide an alternative for treatment of BKVAN in pediatric patients.     

Prevalence and subtypes of BK virus in pediatric renal transplant recipients in Russia

BKV reactivation is associated with impaired graft function in kidney transplant patients. The objective of our study was to determine the prevalence of BKV infection in consecutive pediatric kidney transplant recipients at our center. Fifty-eight pediatric kidney transplant recipients were studied. The mean age at screening was 9.4 ± 2.8 yr, and samples were obtained at a median of 2.4 ± 1.4 yr after transplantation. BKV-DNA was analyzed in urine and plasma by quantitative PCR. Occurrences of BK-DNAuria and BK-DNAemia did not change in the first two yr after transplantation in children and amounted to 21-23% and 7-8%, respectively (p > 0.05). In the third year, the occurrences of BK-DNAuria and BK-DNAemia increased insignificantly to 27% and 9% in the pediatric patients. We also determined the subtypes and subgroups of BK virus isolated from Russian renal transplant recipients and found that BKV isolates were composed of subtypes Ib-2 and IV/c2. The data we obtained indicate that although only 5% of BKVAN cases occurred between years two and five post-transplantation, it seems necessary to regularly monitor pediatric patients for BKV infection through the third year after transplantation.     

BK virus nephropathy in the native kidneys of a pediatric heart transplant recipient

Sahney S, Yorgin P, Zuppan C, Cutler D, Kambham N, Chinnock R. BK virus nephropathy in the native kidneys of a pediatric heart transplant recipient.
Pediatr Transplantation 2010:14:E11–E15. © 2009 Wiley Periodicals, Inc. Abstract: BK virus is a human polyoma virus that may cause nephropathy in immunosuppressed patients. It is a well‐recognized cause of renal allograft dysfunction and allograft loss in renal transplant recipients, but it is an infrequent cause of nephropathy outside this setting. There are a few case reports of BK virus nephropathy in the native kidneys of immunosuppressed adult patients with non‐renal transplants, but so far it has not been reported in pediatric non‐renal solid organ transplant recipients. We report a case of a seven‐yr‐old heart transplant patient who was diagnosed with BK virus nephropathy, eight months after his second heart transplant. Despite intervention, his renal dysfunction progressed to renal failure. He is currently receiving maintenance hemodialysis and awaiting renal transplantation. It is important to recognize BK virus infection as a possible cause of renal dysfunction in immunosuppressed children who are non‐renal transplant recipients.     

Surveillance renal transplant biopsies and subclinical rejection at three months post-transplant in pediatric recipients

Subclinical acute rejection (SCR) has been increasingly recognized in adult renal transplant recipients with the advent of surveillance biopsies. However, in children, surveillance biopsies are not routinely performed at most centers. Therefore, the incidence, predisposing factors, treatment, and clinical outcomes of SCR remain unclear in children. From August 2004 to December 2005, we performed 36 protocol biopsies at three months post-transplantation. All patients had received induction therapy with basiliximab and were maintained on prednisone, MMF, and tacrolimus. Sixteen cases of SCR were detected by biopsy (44%). Age, gender, race, donor source, or serum creatinine did not discriminate between children with SCR and those with normal biopsies. All cases of SCR were treated with high doses of methylprednisolone. At one yr post-transplant, renal function was similar in children with SCR to those with normal surveillance biopsies (p = 0.62). Because of the high incidence of SCR, the maintenance dose of MMF was increased by 50% in 20 children transplanted after December 2005. This resulted in a significant decline in the incidence of SCR from 44 to 15% (p < 0.05). However, the incidence of polyomavirus (BK) viremia also increased significantly in these children (p < 0.005). Conclusion: A high incidence of SCR was found on surveillance biopsies at three months post-transplant and could not be predicted by age, gender, race, donor source, or serum creatinine. The occurrence of SCR declined significantly by increasing the dose of MMF, but resulted in an increase in BK viremia. We conclude that surveillance biopsies provide valuable information in the management of pediatric renal transplant recipients. Increasing immunosuppression to avoid SCR should be weighed against the risk for infection.     

BK polyomavirus infection in pediatric heart transplant recipients: a prospective study

BKV infection and nephropathy complicate pediatric HTx, but the incidence and time course of the disease are unknown. We assessed the incidence of BKV infection and its association with kidney dysfunction in pediatric HTx recipients. A single center prospective study compared pediatric (<18 years) HTx recipients, with and without BKV infection, who received an allograft between September 2013 and December 2014. Screening of urine for BKV was performed prior to transplant, and at week 1, and at months 3, 6, 9, 12, and 15 months post‐transplantation. Serum for BKV DNA was assayed if BK viruria was present. Statistics included Fisher's exact test and Student's t test. Twelve patients were enrolled. Two patients were removed per parent request. Two (20%) had BK viruria and one (10%) had BK viremia. No patients developed BKVN. BK viruria was present within 2 months following transplantation. There were no identifiable risk factors for BKV infection and no statistically significant difference in renal function between the groups; however, there was a trend toward worsening renal function in those with BKV infection. BKV infection can occur early following heart transplantation. Screening for BK viruria should be considered in HTx recipients.     

Intravesicular cidofovir for BK hemorrhagic cystitis in pediatric patients after hematopoietic stem cell transplant

BK virus hemorrhagic cystitis is a complication of HCST. Response to IV cidofovir is unpredictable, and treatment carries risk of toxicity. We report the largest series of pediatric patients with BKHC after HSCT successfully treated with intravesicular cidofovir. There was no significant decrease in urine or plasma BK PCR. There was significant decrease in pain score on days 3 and 7, with associated decrease in morphine use. No patients experienced toxicities associated with IV cidofovir. Intravesicular cidofovir appears to be safe and effective for symptomatic treatment of BKHC in pediatric patients after HSCT.     

Polyomavirus (BK) in pediatric renal transplants: evaluation of viremic patients with and without BK associated nephritis

Polyoma BK virus (BKV) is emerging as a significant complication in renal transplantation, which may lead to renal dysfunction and graft loss caused by BK nephritis (BKN). We report the management and outcome of 20 children who developed BK viremia. Serum polymerase chain reaction (PCR) for BKV DNA was measured monthly for the first year in transplant recipients and every six months thereafter, or for unexplained creatinine elevation. With seroconversion to +PCR, patients were managed with reduction of immunosuppression. Renal biopsy was performed if PCR or creatinine did not improve. From June 2003 to January 2006, 20 children seroconverted for BKV at 23 to 1410 days post-transplant (mean 467 days). Sixteen underwent renal biopsy. Eight displayed BKN, three acute rejection and five were normal. Patients with BKN displayed higher PCR and serum creatinine and presented later than children with viremia without BKN. There were no differences between the two groups for age, gender, donor source or immunosuppression. Seven children with BKN received treatment with cidofovir. Thirteen patients (65%) remained PCR+ after reduction of immunosuppression or treatment with cidofovir. Renal function was stable in 16 children (80%) at 13 +/- 6 months after seroconversion. Four patients with BKN demonstrated progressive loss of renal function. BKV infection in children can occur as an early complication or may develop years after transplantation. Patients with BKN presented later and displayed higher viral loads and serum creatinine than viremic patients without BKN. Children with BKN remained PCR+ despite reduction of immunosuppression or treatment with cidofovir and were at greater risk for loss of renal function.     

Intravenous immunoglobulin therapy in the treatment of BK viremia and nephropathy in pediatric renal transplant recipients

Anyaegbu EI, Almond PS, Milligan T, Allen WR, Gharaybeh S, Al‐Akash SI. Intravenous immunoglobulin therapy in the treatment of BK viremia and nephropathy in pediatric renal transplant recipients.
Pediatr Transplantation 2012: 16: E19–E24. © 2010 John Wiley & Sons A/S. Abstract: Polyoma BKVN is a significant cause of allograft dysfunction and loss in renal transplant recipients. Reduction in immunosuppression is accepted as first‐line therapy to decrease viral load and prevent allograft injury and dysfunction. We report our experience with persistent BKV after reduction in immunosuppression followed by successful clearance of BKV in three pediatric renal transplant recipients and histological resolution of BKVN in a fourth patient following therapy with IVIG. Once BKV was detected, immunosuppression was reduced and BKV was monitored until clearance was achieved. All four patients were given IVIG in a dose of 2 g/kg. Allograft function remained stable in all patients. Early routine screening for BKV allows early intervention to prevent the development of BKVN and permanent allograft damage. While immunosuppression reduction is a logical first‐line therapy, second‐line therapy is not well established. IVIG seems to be an effective treatment for persistent BKV after reduction in immunosuppression and for BKVN and can therefore be considered as a therapeutic option in these patients.     

Native BK viral nephropathy in a pediatric heart transplant recipient

Ali FN, Meehan SM, Pahl E, Cohn RA. Native BK viral nephropathy in a pediatric heart transplant recipient.
Pediatr Transplantation 2010: 14:E38–E41. © 2009 Wiley Periodicals, Inc. Abstract: BK viral nephropathy is a well‐documented clinical entity in kidney transplant recipients and a significant cause of morbidity and allograft loss in affected patients. BK viral nephropathy in native kidneys of non‐kidney transplant recipients is relatively uncommon, but has been reported in adult patients. We report the occurrence of BK viral nephropathy in a pediatric heart transplant recipient. A 10‐yr‐old boy with past history of Ewing’s sarcoma underwent heart transplantation for dilated cardiomyopathy induced by previous chemotherapy with doxorubicin. Post‐transplant course was complicated by grade 3A rejection and CMV colitis. He was diagnosed with native BK viral nephropathy approximately 18 months post‐transplant due to mild, but persistent, elevation in serum creatinine associated with proteinuria. BK viral nephropathy affects non‐kidney transplant recipients, and a high index of suspicion is necessary for early diagnosis and management of this condition.     

BK virus nephropathy in a pediatric patient after hematopoietic stem cell transplantation

We report the case of a seven‐yr‐old Caucasian girl who presented with progressive deterioration of renal function 13 months after HSCT for myelodysplastic syndrome. BK virus nephropathy was suspected and confirmed. After reduction of immunosuppression and treatment with IVIG, leflunomide, ciprofloxacin, and cidofovir, clearance of BK virus from blood was achieved, and further progression or renal failure was prevented. We believe that BK virus nephropathy should be considered in cases of renal function deterioration in all immunocompromised patients.     

Transplant renal artery stenosis in a child with BK nephropathy

TRAS and BK nephropathy are known complications of RT, but the association between both has not been reported. A 2‐year‐old girl underwent a deceased donor renal transplant from a 20‐year‐old donor, along with bilateral native nephrectomies. She had a DGF due to a renal artery thrombus and required thrombectomy with re‐anastomosis. Heparin and aspirin were used. Immunosuppressive agents included thymoglobulin, steroid, tacrolimus, and MMF. CMV and EBV DNA PCRs were negative, but she developed BK viremia at 2 months with stable allograft function. Immunosuppression was reduced, and leflunomide was initiated. Blood pressures were well controlled on low‐dose amlodipine. Five months after RT, she presented with hypertensive emergency, following a respiratory infection, and required dialysis for oliguric acute kidney injury. Allograft biopsy showed evidence of BK nephropathy. Immunosuppression was further minimized. Doppler renal US and renal artery duplex studies were both suggestive of TRAS. Angiogram showed severe proximal anastomotic TRAS (>95% occlusion). PTA with stenting was done with immediate improvement in the blood flow and reduction in the pressure gradient. BPs and renal function normalized. Ten months post‐RT, she remains normotensive with stable renal function and resolution of BK viremia. Although ureteral stenosis and nephropathy are known to occur with BK infection, TRAS is an interesting association and possibly suggest the tropism of BK virus to the vascular endothelial cells. Timely recognition and management of both is important to prevent uncontrolled hypertension and allograft dysfunction.     

Use of intravenous immunoglobulin in a highly sensitized pediatric renal transplant recipient with severe BK DNAemia and rising DSA

BK DNAemia in renal transplant recipients is a significant cause of allograft dysfunction and can lead to graft loss due to BK polyomavirus–associated nephropathy or to graft rejection due to immunosuppression reduction. Currently, the first‐line treatment for BK DNAemia is immunosuppression reduction. Second‐line treatment for BK DNAemia has not been well‐established. In this report, we present a case of a highly sensitized second‐time pediatric renal transplant recipient with severe and persistent BK DNAemia and rising DSA, who was treated with IVIG and subsequently found to have clearance of BK viremia with concomitant reduction in DSA.     

BK virus nephropathy in a pediatric autologous stem-cell transplant recipient

BK virus (BKV) is an increasingly identified cause of pathology in immunocompromised transplant recipients. BKV is a well-known cause of graft dysfunction following renal transplantation and has also been reported in the native kidneys of other solid organ recipients. Less commonly, BKV nephropathy occurs in allogeneic stem-cell transplant (SCT) recipients. We now describe the first reported case of BKV nephropathy after pediatric autologous SCT.