Monitoring of Polyomavirus BK Replication and Impact of Pre-Emptive Immunosuppression Reduction in Renal-Transplant Recipients in China: A 5-Year Single-Center Analysis.
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Background:A 1-year, single-center trial demonstrated that monitoring and preemptive of immunosuppression reduction were associated with resolution of viremia.Our 5-year prospective subsequent study was conducted to determine the long-term patient/graft survival and outcome of BK viremia and BK virus-associated nephropathy (BKVAN) in renal transplant recipients under the impact of intensive monitoring and reduction of maintenance immunosuppression. Methods:Quantitative BK virus (BKV) DNA surveillance in plasma/urine and cytological test in urine were performed at 1, 3, 6, 9, and 12 months after transplantation in 229 kidney recipients.Patients with BK viremia and BKVAN treated with 30% to 50% reduction in doses of tacrolimus (Tac) or/and mycophenolate mofetil(MMF) without antiviral therapy and were monitored for BKV every 3-6 months. All the patients were followed for 5 years. Results:Overall 5-year patient survival was 95.6% and graft survival was 92.1%. There were no differences in patient/graft survival, renal function, and rejection rate by presence of decoy cells, BK-viruria, viremia, or BKVAN. Multivariate analysis showed that Tac(OR, 2.9; P=0.032)and deceased kidney donation(OR, 2.1; P=0.071) were risk factors for BK viremia. After reduction of immunosuppression, viremia (n=38) resolved in 100%, without increased acute rejection. In the duration of follow-up 2-5 posttransplant years, BK viremia was not observed again in the BK viremic patients (n=30) without BKVAN. BKVAN was diagnosed in 7 cases(3.1%). The treatment of immunosuppression reduction was effective. All the BKVAN patients cleared viremia with a mean time of 5.9 months (range 1-15 months). Three of 7 BKVAN patients cleared viruria. A repeated renal biopsy was performed in two patients and revealed resolving BKVAN. There was no decline in estimated glomerular filtration rate over time from1 month(53.1mL/min) to 5 years(58.5mL/min) after transplantation (P=0.960). Conclusions:Monitoring and preemptive of immunosuppression reduction resulted in the successful resolution of BK viremia, showed effective in BKVAN recipients at the early stage with excellent graft survival and renal function at 5-years.Keywords:
Immunosuppression
Viremia
Polyomavirus Infections
Introduction: BK-virus (BKV) infection may lead to polyomavirus BK-associated nephropathy (PVAN), which is a serious complication after renal transplantation (RTX) and may lead to allograft loss. The exact etiology is still unknown. Concerning BK-seropositivity of more than 90% in general population PVAN could either be caused by a new infection or reactivation of the virus from the recipient or by augmented replication of the persistent virus in the allograft. Aim of this retrospective single-center analysis was to detect the prevalence of BK viremia of kidney transplant recipients and search the main infection source of polymaviruses in transplanted kidneys. Methods: BKV-screening was made by serum-PCR in 506 patients (pts) who were transplanted during January 2005 and June 2011. Furthermore we examined the BK viremia of the recipients who received the “partner kidney” from the same donor of the BKV positive patients and compared them with recipients from the “partner kidney” of a negative group. Results: From 506 kidney transplant recipients with at least one assessment of BK-PCR, PCR became positive (VL > 500 cop/ml) in exactly 100 pts (19.8%). In 33 cases from these pts the contralateral kidney was also transplanted in our centre and the BK viremia of these recipients could be followed up. In 18 (54.6%) recipients of the contralateral kidney (“partner recipient”) BK viremia could also be detected. In 10 (30.3%) “partner recipients” the BKV-PCR was negative and in 5 (15.2%) cases no BKV-PCR was made. In a coincidentally chosen BKV negative group of 100 pts, in 27 cases the contralateral kidney was transplanted in our centre and therefore could be followed up. In only 1 (3.7%) case positive BK viremia could be found. In 18 (66.7%) BKV-PCR was negative and in 8 (29.6%) cases no BKV-PCR was made. Conclusion: The prevalence of BK viremia in kidney transplanted patients in our centre is high (19.8%). In 54.6% of the BKV positive cases, where the contralateral kidney was also transplanted in our centre, the recipient of the “partner recipients” also developed a BK viremia compared to only 3.7% BKV positive cases in recipients of the contralateral kidney from our BKV negative patients. This indicates that infected donor organs could be mainly responsible for BK viremia and therefore for PVAN. Multi-centre studies with more data are necessary to confirm this assumption.
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Abstract Background Reducing immunosuppression can effectively treat BK viremia (BKV) and BK nephropathy, but has been associated with increased risks for acute rejection and development of donor‐specific antibodies (DSA). To date there have been no systematic evaluations of re‐escalating immunosuppression in transplant patients with resolving BKV. Importantly, the safety of this approach and impact on graft survival is unclear. Methods We performed a single‐center retrospective review of kidney transplant recipients between July 2011 and June 2013 who had immunosuppression reduction after developing BKV (plasma PCR ≥ 1000 copies/ml). Changes in immunosuppression and patient outcomes were tracked until occurrence of a complication event: biopsy‐proven acute rejection (BPAR), detection of de novo DSA, or recurrent BKV. Patients were grouped according to whether or not net immunosuppression was eventually increased. Results Out of 88 patients with BKV, 44 (50%) had net immunosuppression increased while the other 44 did not. Duration of viremia, peak viremia, induction, and sensitization status were similar between the two groups. In a Kaplan‐Meier analysis, increasing immunosuppression was associated with less BPAR ( P = .001) and a trend toward less de novo DSA development ( P = .06). Death‐censored graft survival ( P = .27) was not different between the two groups. In the net immunosuppression increase group, recurrent BKV occurred in 22.7% without any BKV‐related graft losses. Conclusion These findings support potential benefits of increasing immunosuppression in patients with low‐level or resolved BKV, but prospective trials are needed to better understand such an approach.
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Background Immunosuppression reduction for BK viremia is associated with de novo humoral responses, which are a risk factor for rejection and graft loss. In this pilot project, we tested a protocol of immunosuppression resumption to standard dose after viral clearance for optimal protection against rejection in patients undergoing treatment for BK viremia. Methods Thirty-six consecutive kidney transplant recipients who developed BK viremia from 7/1/2014 until 11/18/2016 underwent immunosuppression reduction. After four weeks of absent viremia, mycophenolate mofetil (MMF) was increased by 500mg/day every two weeks up to standard dosage, followed by increase of tacrolimus trough levels to 5-7ng/mL. If viremia recurred during the increase, immunosuppression was reduced in this same stepwise fashion, with stepwise increase again after two months of negative viremia. Results Mean tacrolimus trough level (ng/mL) was 8.3+2.7 at viremia onset, 5.3+3.6 at resolution, and 5.6+2.0 at study end date. Mean daily dose (mg) of MMF was 1574+355 at onset, 910+230 at resolution, and 1377+451 at study end date. Only one patient developed low level viremia recurrence (peak 2875 copies/mL) during the period of immunosuppression resumption that ultimately resolved. Conclusions The results of our pilot project indicate that following BK viremia resolution, resumption of standard immunosuppression can be achieved safely without BK viremia recurrence. Larger trials with long-term follow up are required to determine whether such an approach improves long- term graft survival. This work was supported by the Gatorade Trust through funds distributed by the University of Florida, Division of Nephrology, Hypertension, and Renal Transplantation, and the Central Florida Kidney Center, Inc. Eminent Scholar Chair in Nephrology and Hypertension.
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Abstract Background Immunosuppression reduction for BK viremia is associated with de novo humoral responses, which are a risk factor for rejection and graft loss. In this pilot project, we tested a protocol of immunosuppression resumption to standard dose after viral clearance for optimal protection against humoral immunity in patients undergoing treatment for BK viremia. Methods Thirty‐six consecutive kidney transplant recipients who developed BK viremia from 7/1/2014 to 11/18/2016 underwent immunosuppression reduction. After 4 weeks of absent viremia, mycophenolate mofetil (MMF) was increased by 500mg/day every 2 weeks up to standard dosage, followed by increase of tacrolimus trough levels to 5‐7 ng/mL. If viremia recurred during the increase, immunosuppression was reduced in this same stepwise fashion, with stepwise increase again after 2 months of negative viremia. Results Mean tacrolimus trough level (ng/mL) was 8.3 ± 2.7 at viremia onset, 5.3 ± 3.6 at resolution, and 5.6 ± 2.0 at study end date. Mean daily dose (mg) of MMF was 1574 ± 355 at onset, 910 ± 230 at resolution, and 1377 ± 451 at study end date. Only one patient developed low level viremia recurrence (peak 2875 copies/mL) during the period of immunosuppression resumption that ultimately resolved. Conclusions The results of our pilot project indicate that following BK viremia resolution, resumption of standard immunosuppression can be achieved safely without BK viremia recurrence. Larger trials with long‐term follow up are required to determine whether such an approach improves long‐term graft survival.
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Abstract Background BK polyomavirus virus ( BKP yV) screening and immunosuppression reduction effectively prevent graft loss due to BKP yV‐associated nephropathy ( BKPVAN ) during the first year after transplantation. The aim of our study was to evaluate the impact of this infection during longer follow‐up periods. Methods We reviewed the outcome of our screening and immunosuppression reduction protocol in 305 patients who received a kidney transplant between March 2008 and January 2013. Quantitative BKP yV DNA surveillance in plasma was performed at 1, 2, 3, 6, 9, and 12 months after transplantation. Patients with significant viremia and/or biopsy‐proven BKPVAN were treated with immunosuppression reduction and leflunomide. Results During the first post‐transplant year, 24 patients (7.9%) developed significant viremia at a median time of 95 days, and 18 patients had BKPVAN ; 23 of the 24 (7.5%) were treated according to our protocol (group BKV +); 225 patients (73.8%) did not develop any BK viremia (group BKV −). Allograft function was similar in both groups at 1 month post transplantation ( P =.87), but significantly worse at 1 year in the BKV + group ( P =.002). Thereafter, kidney function stabilized in the BKV + group and no differences in patient and graft survival were seen between the groups after a median follow‐up of 4 years. Conclusions We confirm the early occurrence of BKP yV replication after transplantation and the short‐term decline in renal function. However, early detection of BKP yV replication, prompt diagnosis, and reduction in immunosuppression may offer long‐term benefits for graft function.
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The diagnosis of BK virus nephropathy is based on renal biopsy findings, and the diagnosis of presumptive BK virus nephropathy is made by sustained plasma BK virus DNA loads of > 4 log10 copies/ml. However, the BK virus plasma viral load cutoff of 4 log10 copies/ml may underestimate the diagnosis of BK virus nephropathy. In this study, we evaluated the clinical significance of BK viremia in kidney transplant recipients. From January 2010 to November 2015, we experienced 8 kidney transplant recipients who developed BK viremia. We retrospectively analyzed these recipients, focusing on the plasma BK viral load at onset of BK viremia, time to BK viremia after transplantation, frequency of BK virus nephropathy, and our treatment for BK viremia. The median plasma BK virus polymerase chain reaction at the diagnosis of BK viremia was 1600 copies/ml (370–9400 copies/ml). The median time to BK viremia after transplantation was 10.9 months (1.4–67.9 months). Three patients were associated with BK virus nephropathy on biopsy. Clearance of BK viremia was observed in all of these cases after intervention. Our study demonstrated that intervention in BK viremia with a viral load of < 4 log10 copies/ml may be needed to prevent the development of graft dysfunction and BK virus nephropathy in kidney transplant recipients.
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Mizoribine
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BK virus (BKV) reactivation is a serious complication after kidney and kidney-pancreas transplantation, with the majority of cases occurring during the first 6 months after transplant. There are limited data on the outcome of early versus late BKV reactivation after kidney transplantation. This study included 609 kidney and kidney-pancreas transplant recipients screened for BKV after transplantation using qPCR tests in blood. 163 patients (26.7%) developed BK viremia; of whom 106 patients (65%) were within the first 6 months after transplant (early BK viremia) (median3 months, IQR 1.8-4.2 months), and in 57 patients (35%) were beyond 6 months post-transplant (late BK viremia) (median 13 months, IQR 8.6-22 months). Patients who developed early BK viremia were more likely to have high BK viral load [ ≥10,000 copies/mL] (RR= 16.3, 95% CI 7.1-44.3, P<0.001) compared to the late BK viremia group. Moreover, early BK viremia was associated with significantly worse graft function; compared to the late BK viremia group and patients who did not develop BK viremia - at 1 year (eGFR 46, 51, and 52 ml/min/1.73 m2, respectively, p=0.01) and 2 years post-transplant (eGFR 46, 50, and 51 ml/min/1.73 m2, respectively, p=0.02). We also found a trend toward higher risk of graft rejection in the early BK viremia group compared to the late BK viremia group and patients who did not develop BK viremia using Cox time dependent model (14% vs 7% and 8% respectively (RR= 1.8, 95% CI 0.97-3.2, p=0.06). Patient and graft survival were comparable in the 3 groups using Kaplan Meir analysis (p= 0.1, 0.6 respectively). Early BKV reactivation is 16 folds more likely to present as high viremia than late BKV reactivation, is associated with worse graft function, and a trend to higher risk for graft rejection. In the current era of BKV surveillance, BK viremia (early and late) is associated with excellent patient and graft survival perhaps secondary to early diagnosis and intervention. Overall, the current data supports the role of BKV surveillance; especially within the first 6 months post-transplant.
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Polyoma virus (BK subtype) is one of the most common viral infection among kidney transplant recipients. In the first-year post-transplant, up to 30% of patients will develop BK viremia, while BK nephropathy occurs in 2-12%. Polyoma virus reactivation often reflects excessive immunosuppression. As patients are asymptomatic, viral load monitoring is mandatory and diagnosis is confirmed by kidney biopsy. Besides solid organ transplantation, cases of BK virus infection in patients with immunosuppression of other causes have been reported in the literature.
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BK virus is a polyomavirus that can cause nephropathy and graft loss after kidney transplant. The aim of our study was to screen the BK viremia prevalence, to understand the value of the inter-vention for BK virus nephropathy, and to determine the risk factors associated with BK viremia after kidney transplant in our center.Our retrospective cross-sectional study included 91 adult kidney transplant recipients who were seen between 2015 and 2017 and who had follow-up from 1 month to over 2 years. BK viremia was evaluated by use of plasma quantitative polymerase chain reaction. The prevalence of BK viremia and the clinical treatments and outcomes of BK virus nephropathy were assessed.The prevalence of BK viremia was 5.5% (5/91 patients). BK virus nephropathy was confirmed by allograft biopsy in 4.4% (4/91 patients) of all patients. Delayed graft function was found to be an independent risk factor for BK viremia (P < .001). Patients with BK viremia had significantly higher serum creatinine levels (P = .04). Patients who were diagnosed with BK viremia at 1 to 5 years after kidney transplant had higher serum creatinine (P = .02) and uric acid levels (P = .02). After reduction or discontinuation of calcineurin inhibitor, BK virus was cleared in all patients with BK virus nephropathy, with higher level of serum creatinine but no graft loss.Delayed graft function was considered as a risk factor for viremia. Early detection of BK viremia replication is important. The strategy of reduction of immunosuppression was effective for BK virus nephropathy and graft function improvement.
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