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Author: Sayali Thakare, MD
Expert Reviewer: Sumit Mohan, MD
Illustrations by: Corina Teodosiu, MD
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.
The discovery of BK Polyomavirus (BKPyV) back in the 1970s appears to have preceded the knowledge of its complete disease spectrum in humans. The first case of BKPyV infection was described in a 39-year-old Sudanese kidney transplant recipient (KTR), who presented to the St. Mary’s hospital, London, at 3½ months post-transplant with anuria due to transplant ureteral stenosis. Early in the course of admission, urine samples showed presence of inclusion bearing cells. Also prominent in these samples were a large number of virus particles having a morphology similar to polyomaviruses of the Papovaviridae family. The recipient was treated for two episodes of mild rejection on the 5th and 110th day after transplant. He was otherwise maintained on prednisone and azathioprine, the latter popularized by Sir Roy Calne through his pivotal research on immunosuppressive agents spanning two continents. The classic account of this discovery published in The Lancet in 1971 takes us to the Virus Research Laboratory, London, where the virologist, Dr. Sylvia Gardner, and her team employed a remarkable battery of tests to establish this as a new human polyomavirus. In an era when transplantation was making great strides across the globe, these futuristic appearing tests complemented the zeitgeist perfectly and included electron microscopy of urine and surgical specimens, immune-electron microscopy, viral isolation, demonstration of cytopathic effects, haemagglutinin inhibition, and rising antibody titers in post-transplant sera. Famously, the virus was assigned a provisional name using the patient’s initials and came to be known as BK virus.
The recipient underwent excision of a large segment of the donor ureter and the involved bladder, followed by a uretero-ureteral anastomosis to the native ureter. This surgical revision led to an improvement in graft function. Unfortunately, being a developing technique, kidney biopsy was not widely utilized then. Thus, the renal pathology of BKPyV infection remained elusive until much later in 1995, when BKPyV associated interstitial nephritis (BKPyVAN) was reported for the first time in a 34-year-old male with allograft dysfunction at 38 weeks after transplant. A series of such reports were published in the following years. Asymptomatic infection, hemorrhagic cystitis and recently urothelial cancer are other presentations known to be associated with BKPyV reactivation (Figure 1).
Figure 1. Manifestation of BKpY in kidney transplant recipients
BKPyV is widely distributed in the human population. It is a small, non-enveloped, double-stranded, icosahedral DNA virus of the polyomavirus family and is one amongst the four polyomaviruses known to be pathogenic to humans. The primary route of transmission is mucosal contact. Human BKPyV infection is characterized by a lifelong latency or persistent infection within the host, chiefly in the kidneys and urothelium. Consequently, BKPyV is also transmitted through donor kidneys.
More than 90% of healthy individuals acquire BKPyV infection before adolescence. Yet, only a fraction of patients, for instance, 7% of seropositive immunocompetent healthy blood donors shed virus in the urine without any systemic affliction. BKPyV specific seroprevalence wanes in the elderly due to declining immunity. Cellular immunity is critical for control over viral replication. Innate immunity is the first line of defense. Dendritic cells of the innate immunity pathway serve to induce adaptive immune responses. CD4 and CD8 T cells both play a crucial role. The BK capsid proteins, large T antigen, and non-structural proteins elicit T-cell responses. A shorter time (<1 month) to development of T-cell response correlates with clearance of viremia. Latent viral reactivation is kept in check by BKPyV-specific memory T-cells. Viral kinetics are valuable in diagnosing BKPyVAN and prognostication. Inter-variability amongst commercially available PCR assays is high and often prevents meaningful comparison of viral kinetics.
Pathogenesis of BKPyV associated nephropathy (BKPyVAN) centers around activation of viral replication when the host is immunocompromised or diseased due to other causes. Ensuing viral replication and its cytopathic effects cause damage to the renal tubular epithelium (Figure 2). Resulting inflammation leads to activation of pro-fibrotic pathways with TGF-beta, MMP-2, MMP-9, matrix collagens. Major groups of messenger RNAs are upregulated, many sharing commonality with T-cell mediated rejection (TCMR). Challenges to interpretation of biopsy findings include tissue sampling variation and concomitant rejection process. The 2018 Banff Classification of Polyomavirus Nephropathy by Nickeleit et al (validated in a large multinational cohort) is used most often today and has unified reporting practices across the globe. It utilizes two variables that significantly influence the allograft function- 1) polyomavirus replication/load (fraction of tubules with morphologic evidence of polyomavirus replication/SV40 staining) and 2) interstitial fibrosis scores (notably not interstitial inflammation).
Figure 2. BKPyV pathogenesis
The early reports of BKV infection estimated 3%-5% rates of tubulo-interstitial nephritis or ureteral stenosis at 2-60 months (median, 9 months). The rate of graft loss in this era was 45%. Subsequent studies from wider geographical regions reported the development of BKPyV viruria and viremia in 10-35% of KTRs, and that of BKPyVAN as 1-10% (Table 1). Though the incidence of viruria/viremia is small, the implication for graft loss (up to 15%) and rejection (15- 25%) is significant for those who develop BKPyVAN. Increased risk of de-novo DSAs has been documented in KTRs presumably because of therapeutic reduction in immunosuppression. Most relevant risk factors for developing BKPyVAN are male sex, deceased donor, older donor, elderly and pediatric age group, history of a previous transplant, ureteral stent use, delayed graft function and acute rejection. In the absence of universal surveillance, presence of risk factors may suitably prompt transplant clinicians to look for BKPyVAN as a cause of allograft dysfunction.
The treatment practices vary considerably across different regions as well. Therapeutic decisions need to be individualized taking into account the severity of infection versus the immunological risk of developing rejection. In the absence of effective anti-BKPyV therapy, immunosuppressant dose reduction is advised when the plasma viral load exceeds 104 copies/mL. However, most real-world practice is rightfully dictated by clinical discretion, especially because BK PCR testing is not standardized and suffers from a wide discordance between laboratories. The WHO international Standard for BKPyV infection was introduced in 2016 to help overcome this limitation. However, apart from the viral load, another caveat is that not all strains of the 4 BKPyV genotypes are equally pathogenic. Also, given the high rate of mutations the resulting genetic instability can give rise to variants difficult to treat.
Restoration of BKPyV specific immune responses leads to the control of infection. Many studies have explored the effect of different strategies for reducing immunosuppression, however no consensus has arisen from existing evidence. Tacrolimus based regimes consistently show a higher risk for BKPyVAN, while conflicting reports exist for others. Conversion to mTOR inhibitors appears to improve graft survival, however long term outcomes need to be evaluated. A study investigating different strategies for reducing immunosuppression in BKPyVAN showed that any sequence and dosage is equally efficacious if it leads to a decrease in viral load. The antiviral drugs leflunomide and fluoroquinolones have not shown benefit. Cidofovir appears to be effective from observational data but is a less popular choice due to concerns of nephrotoxicity. An approach to treatment of BKPyVAN with IVIG has been explored and appears valuable.
Graft failure and loss occur with BKPyVAN, but research gaps exist in the epidemiology of patient risk factors, immunosuppression prescribing patterns, and long-term outcomes. The recent KI Reports study by Gately et al (Figure 3), aims to fill that gap by drawing data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry. This registry is remarkable for containing outcomes of biopsy proven BKPyVAN in 14,697 patients for a study duration of 15 years (2005-2019). The binational ANZDATA registry has been operational since 1977 and collects data on kidney failure and kidney transplants across all centers in these two countries. Median follow-up time of patients in this study was 64.8 months (+/-49.2 months), amounting to a staggering period of 91,306 patient-years of observation. For a time-varying disease such as BKPyVAN, availability of a large patient-time reflects real-world statistics more closely. The cumulative incidence of BKPyVAN in this cohort was 3.3%. Consistent with other data, most cases of BKPyVAN (76%) occurred within the first 12 months of transplant (91.5% within the first 24 months). Median time to nephropathy was 4.8 months (3.1-10.8 months). Interestingly, this cohort showed a decline in incidence of BKPyVAN in the most recent time-tertile of 2015 to 2019.
Visual abstract by Augusto Cesar S Santos Jr MD
The primary outcome of this study was all-cause graft loss. Secondary outcomes were death-censored graft loss and patient death. BKPyVAN was diagnosed as per the Banff Polyomavirus Nephropathy classification system, though indication for each biopsy was not recorded and accuracy of reporting was not independently verified by the registry. A higher rate of graft loss was observed in the BKPyVAN group (35% vs 21%). A higher rate of death was observed in this group too (18% vs 13%), however there were no differences in the cause of death recorded. HR for graft loss was 1.84, indicating an 84% increase in relative risk of graft loss in those developing BKPyVAN. 29% of graft loss was attributable to BKPyVAN. The median graft survival time after diagnosis of BKPyVAN was 10.1 years. Acute rejection was more common in the BKPyVAN group (42% vs 25%), with an almost equal number of rejections occurring before and after the diagnosis of BKPyVAN. Notably, 15% of patients had rejection both before and after BKPyVAN diagnosis. The risk factors for BKPyVAN in this cohort were male sex, older recipient age, recipient blood group AB, increasing donor age, donor blood group B, ethnic mismatch, initial tacrolimus use, and being transplanted at a small volume transplant center.
Approximately half of the patients (51%) underwent a reduction in tacrolimus dosing by 50% after detection of BKPyVAN. The dose was reduced by >50% for 40% of patients and tacrolimus was stopped for the remaining 10%. 6% of patients were converted from tacrolimus to cyclosporine. Mycophenolate was reduced by 50% for 40% of patients, and reduced by >50% or stopped for approximately 30% each. 3-3.5% of patients were initiated on azathioprine or mechanistic target of rapamycin (mTOR) inhibitors. Leflunomide was initiated for 19%. Out of these dose adjustments, only mycophenolate reduction by >50% was found to improve graft survival.
Data from large registries serves to overcome inherent limitations of geographically restricted or insufficiently large cohorts. Large sample size also serves well to pick up smaller statistical effects, even if variability of a given parameter is large. However, the ensemble of BKPyVAN studies are typically marked by heterogeneity that has precluded generalisability (Table 1). Cumulative incidence of BKPyVAN was 3.3% in this study, comparable to 4.5% and 6.6% from the European and OPTN registry data respectively. However, the majority of patients (67.5%) in this study were recipients of deceased donor kidney transplantation with a mean age of 50.1 years in the BKPyVAN group. The incidence of BKPyVAN may be substantially different in other populations where living kidney donations predominate and recipients are of dissimilar age categories, often a decade younger .
Incidence at 5 years dropped in the more recent time tertile (2015-2019), in contrast to other observations, however, both countries Australia and New Zealand presently do not follow an active surveillance strategy for BKPyV infection. Two relatively under-explored risk factors brought forth by this study are association with blood group B, presumably because of HLA variations in study population, and ‘ethnic mismatch’ as a risk factor instead of ethnicity of a given donor or recipient. The ANZDATA does not routinely record other antiviral therapy used for BKPyVAN, inclusion of which would have contributed valuable insight.
There is currently no tool to measure the net state of immunosuppression. As more potent immunosuppressive agents become available, BKPyV infection may re-emerge as a significant cause of graft loss. Surveillance for BK viruria or viremia, though provides an effective tip-off for reducing immunosuppression, may not always help reduce the risk of BKPyVAN. Low level viremia is documented in as high as 83% of KTRs, with 77% of the total cohort experiencing viremia before month 4, pointing towards high yield of surveillance. KDIGO recommends monthly screening for the first 6 months after transplantation, followed by 3 monthly for the next 18 months. However, response to reduction of immunosuppression is unpredictable. This phenomenon may be reflective of the propensity of BKPyV to mutate and acquire strategies to evade host defences. Biological evasions like VP1 escape mutations are harbored in 26-30% of patients with no virological response to modulation of immunosuppressive therapy. Other approaches to fine-tune risk stratification are quantifying neutralizing antibody titer against the donor’s BKV strain, donor antibody screening, tracking changes in cytokine profile, and use of microRNAs. Furthermore, BKPyV immunotherapy via viral capsid epitope vaccine and adoptive T cell therapy are other newer approaches to prophylaxis and treatment.
In the era of precision medicine, knowing is half the battle. The present study is commendable for strengthening current knowledge about incidence, impact on graft function and long-term outcomes in KTRs with BKPyVAN. The study may be looked upon as a Janus point. From the breadth of past evidence on BKPyV infection, we must now veer towards a future where virus specific biomarkers and virus specific immune-therapy are brought into play for personalized decision-making in this disease.
Table 1: Epidemiology of BKPyV infection and BKPyVAN over decades
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.