Incidence of BK with Tacrolimus Versus Cyclosporine and Impact of Preemptive Immunosuppression Reduction

Our purposes were to determine the incidence of BK viruria, viremia or nephropathy with tacrolimus (FK506) versus cyclosporine (CyA) and whether intensive monitoring and discontinuation of mycophenolate (MMF) or azathioprine (AZA), upon detection of BK viremia, could prevent BK nephropathy. We randomized 200 adult renal transplant recipients to FK506 (n = 134) or CyA (n = 66). Urine and blood were collected weekly for 16 weeks and at months 5, 6, 9 and 12 and analyzed for BK by polymerase chain reaction (PCR). By 1 year, 70 patients (35%) developed viruria and 23 (11.5%) viremia; neither were affected independently by FK506, CyA, MMF or AZA. Viruria was highest with FK506-MMF (46%) and lowest with CyA-MMF (13%), p = 0.005. Viruria >/= 9.5 log(10) copies/mL was associated with a 3-fold increased risk of viremia and a 13-fold increased risk of sustained viremia. After reduction of immunosuppression, viremia resolved in 95%, without increased acute rejection, allograft dysfunction or graft loss. No BK nephropathy was observed. Choice of calcineurin inhibitor or adjuvant immunosuppression, independently, did not affect BK viruria or viremia. Viruria was highest with FK506-MMF and lowest with CyA-MMF. Monitoring and preemptive withdrawal of immunosuppression were associated with resolution of viremia and absence of BK nephropathy without acute rejection or graft loss.     

Variability in assessing for BK viremia: whole blood is not reliable and plasma is not above reproach – a retrospective analysis

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

The impact of surveillance and rapid reduction in immunosuppression to control BK virus‐related graft injury in kidney transplantation

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.     

BK viremia is not associated with adverse outcomes in the absence of BK nephropathy

There are limited data regarding the association of different levels of BK viremia and BK nephropathy (BKN), and graft outcomes. We studied the BK plasma PCR levels of all kidney transplant recipients (KTR) transplanted at our institution between 01/01/2006 and 06/30/2014. Patients were divided into groups based on their highest BK plasma PCR level within the first year following transplantation: undetectable, low (<1000 copies/mL), moderate (1000‐10 000 copies/mL), high (>10 000‐100 000 copies/mL), very high (>100 000 copies/mL), and those that had biopsy‐proven BKN. There were a total of 1146 KTR during the study period: 813 with undetectable BK levels and 333 with any detectable BK level (87 with low, 79 with moderate, 88 with high, 34 with very high level BK, and 45 that had BKN). Compared to KTR with an undetectable BK level, incidence of mortality, graft failure, rejections,and infections were not significantly different for those with low, moderate, high, or very high BK level. Patients with BKN had a higher rate of infection and higher rates of total graft failure or death‐censored graft failure compared to those with undetectable BK levels. BK viremia in the absence of BKN does not significantly increase the risk of rejection, infections, or graft failure compared to an undetectable BK level.     

Test performance characteristics of quantitative nucleic acid testing for polyomaviruses in kidney and kidney‐pancreas transplant recipients

Screening for polyoma BK virus (BK) using nucleic testing (NAT) is recommended for kidney and kidney‐pancreas transplant recipients, but the performance characteristics of quantitative BK NAT at different thresholds of plasma BK viral loads are unclear. We aim to evaluate the diagnostic accuracy of quantitative BK NAT as an add‐on test to qualitative polyoma NAT for the diagnosis of BK virus‐associated nephropathy (BKVAN) in kidney and kidney transplant recipients. We calculated the test sensitivity, specificity, and predictive values at the different thresholds of plasma BK viral load for BKVAN. At the recommended threshold of >1 × 10³ serum BK copies/mL serum for test positivity, the sensitivity for BKVAN was 92.9% (95% confidence intervals [CI]: 66.1–99.8) and specificity 79.1% (95%: CI 67.4–88.1), with corresponding positive and negative predictive values of 42.0% (95% CI: 24.8–57.7%) and 98.6% (95% CI: 98.3–99.9%), respectively. The overall area under curve for the quantitative BK NAT was 0.92 (95% CI: 0.85–0.97). Quantitative BK NAT displays properties of high sensitivity and specificity that are fit for purpose as an add‐on test to qualitative polyomavirus NAT for kidney and kidney‐pancreas transplant recipients at risk of BKVAN.     

No clinical benefit of rapid versus gradual tapering of immunosuppression to treat sustained BK virus viremia after kidney transplantation: a single‐center experience

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 (T₀) were similar among patient groups. However, following onset, the dose of MPA at 1 month (P = 0.002) and 3 months (P = 0.005) and Tac T₀ at 1 month (P = 0.030) and 3 months (P = 0.006) were lower in the RT group. This rapid minimization shortened BKV viremia (P < 0.001) and resulted in a better protection of graft function in patients with confirmed BKV‐associated nephropathy (P = 0.033) without impacting 5‐year graft survival. Survival without rejection was similar (P = 0.571), but the RT group had increased the development of de novo donor‐specific antibodies (dnDSAs; P < 0.001). Multivariate Cox analysis identified basiliximab versus Thymoglobulin^® induction [hazard ratio (HR), 3.090; P = 0.001] and the RT strategy (HR, 6.021; P = 0.002) as independently associated with dnDSAs. Compared to a gradual tapering, rapid immunosuppression tapering to treat sustained BKV viremia does not improve medium‐term clinical outcome but increases the risk of developing dnDSAs.     

Remission of polyomavirus-induced graft nephropathy treated with low-dose leflunomide.

Sir, The incidence of polyomavirus (BK) induced allograft nephropathy(PVAN) has gained in clinical importance as a cause of renalgraft dysfunction [1]. Treatment options are at present confinedto reduction of immunosuppression with or without low-dose cidofovir[2]. Leflunomide is an immunosuppressive drug with in vitroand suspected in vivo antiviral