Brian John Nankivell

Background.: BK polyomavirus (BKPyV) is a common opportunistic infection in kidney transplant recipients, typically reactivating in the context of immunosuppression. Although asymptomatic in immunocompetent individuals, reactivation in transplant recipients can cause BKPyV-associated nephropathy (BKPyVAN), a leading cause of graft dysfunction and loss. BKPyV viremia affects approximately 10%–15% of transplant recipients, and once BKPyVAN is established, the risk of graft failure can exceed 50%. The current standard of care involves immunosuppression reduction to restore virus-specific immunity, but this approach increases the risk of acute and chronic rejection. Intravenous immunoglobulin (IVIg), which contains antiviral and immunomodulatory antibodies, has been proposed as an adjunctive therapy, although evidence supporting its efficacy remains limited to small observational studies. Methods.: The BEAT-BK trial is a multicenter, adaptive, randomized controlled trial comparing standard immunosuppression reduction with or without IVIg in kidney and simultaneous pancreas-kidney transplant recipients with BKPyV viremia or biopsy-confirmed BKPyVAN. The trial will enroll participants aged 2 y and older, randomizing them 1:1 to receive standard care alone or in combination with a total IVIg dose of 2 g/kg for 8 wk. An adaptive Bayesian design will permit interim analyses with the potential for early trial success or futility. Results.: The primary endpoint is a composite ordinal outcome at 12 wk, incorporating death, graft loss, estimated glomerular filtration rate decline, acute rejection, viral load, and degree of immunosuppression reduction. Secondary outcomes include viral clearance, development of BKPyVAN and donor-specific antibodies, infections, malignancy, quality of life, and cost-effectiveness. Conclusions.: This trial will provide the first high-quality evidence on the role of IVIg in BKPyV management and inform clinical decision-making in posttransplant care.

Background.: BK polyomavirus (BKPyV) reactivation causes a destructive allograft nephropathy (BKVAN) with limited treatment options. Quantitative nucleic acid testing (QNAT) of BKPyV-DNA in blood within screening programs monitors for viral reactivation but has imprecise real-world authentication. Methods.: This prospective, single-gate, single-center, population-based cohort study evaluated the test performances of QNAT (the index test) against biopsy-proven BKVAN, verified by universal Simian virus 40 T antigen (SV40T) immunohistochemistry (the optimal reference test), in 5339 consecutive kidney transplant samples. Results.: BKVAN occurred in 205 tissue samples (3.8%) obtained from 1542 recipients (6.9%); classified as polyomavirus nephropathy class 1 in 26.3%, class 2 in 67.8%, and late class 3 in 5.9%. Contemporaneous QNAT⁺ was detected in 12.7% of cases and was associated with viremia persistence, SV40T⁺, and cytopathic effect using multivariable analysis. The sensitivity of 97.7% and specificity of 90.7% for QNAT⁺ to predict BKVAN were unaffected by assay methodology. SV40T⁺ BKVAN was QNAT⁺ in all patients except for 6 false-negative cases. A negative qualitative NAT during protocol surveillance sampling (n = 3667) with a specificity of 90.7% demonstrated a 99.9% negative predictive value for excluding BKVAN at a 2.6% prevalence. In contrast, QNAT exceeding 1.0E+04 BKPyV-DNA copies/mL in viremic patients (n = 679) showed a 56.3% sensitivity and a 54.6% positive predictive value. Mild BKVAN was often misclassified, with a positive likelihood ratio of 2.9. Conclusions.: Test performance of QNAT in transplant recipients varies markedly according to clinical context. A negative QNAT in surveillance programs reliably rules out BKVAN. However, although positive results confirm BKV reactivation, QNAT levels could not accurately distinguish tissue-invasive infection at any threshold value.

Purpose of review: The Banff schema uses combinations of pathological lesions at predefined thresholds to diagnose of T cell rejection (TCMR) and grade its severity. Constant definitional changes have caused confusion among clinicians and pathologists. This review describes the evolution of lesion definitions and the rationale for the minimal thresholds. Recent findings: The minimal diagnostic threshold for borderline TCMR has been reset to original Banff i1/t1, where isolated tubulitis is now excluded. Arteritis can be mediated by either Grade II TCMR or caused by donor specific antibody as antibody-mediated vascular rejection. The conservative threshold for chronic active TCMR diagnosis uses moderate total and scarred inflammation with tubulitis has been challenged by recent longitudinal data to suggest lower thresholds including i-IFTA=1 as clinically relevant. Summary: Minor changes in the threshold ruleset can cause substantial alterations in the final pathological diagnoses. While minimal thresholds for borderline and active TCMR have now stabilized, future changes are likely for chronic active TCMR pending confirmatory research.

Background.: The biological effects of SARS-CoV-2 infection in transplanted kidneys are uncertain with little pathological information. Methods.: This single-center, prospective observational study evaluated kidney transplant biopsies from recipients of deceased donors with COVID-19, current recipients contracting SARS-CoV-2 Omicron variant in 2022, against prior BK virus (BKV) infection and uninfected (without SARS-CoV-2 or BKV) samples, as respective positive and negative comparators (n = 503 samples). Results.: We demonstrated nonvirus tubular injury in implanted tissue from infected donors and prevalent recipients with mild acute COVID-19 and acute kidney injury, excluding direct viral infection as a cause of kidney damage. COVID particles were absent in 4116 ultrastructural images of 295 renal tubules from 4 patients with acute COVID-19. No viral cytopathic effect, viral allograft nephropathy, or SARS-CoV-2 RNA was detected in acute tissues, nor in 128 sequential samples from infected donors or recipients with COVID-19. Following recipient COVID-19 (mean 16.8 ± 12.0 wk post-infection), the biopsy-prevalence of rejection was 33.0% (n = 100 biopsies) versus 13.4% for contemporaneous uninfected controls (n = 337; P < 0.001). Prior COVID-19 was an independent risk factor for incident rejection using multivariable generalized estimating equation adjusted for competing risks (odds ratio, 2.195; 95% confidence interval, 1.189-4.052; P = 0.012). Landmark and matched-pair analyses confirmed an association of SARS-CoV-2 with subsequent transplant rejection, with a similar pattern following BKV infection. Conclusions.: Transplantation from COVID-19+ deceased donors yielded good recipient outcomes without evidence of viral tissue transmission. Acute kidney injury during COVID-19 was mediated by archetypical tubular injury and infection correlated with an increased risk of subsequent rejection.

Background.: Microvascular inflammation (MVI) is an important pathological feature of antibody-mediated rejection (AMR). How posttransplant time affects its clinicopathological expression is little understood. Methods.: This retrospective, single-center study screened 3398 kidney transplant biopsies and dichotomized 202 MVI ≥ 2 (Banff glomerulitis + peritubular capillaritis ≥ 2) samples by 9-mo median incidence time for comparison. Results.: The prevalence of MVI ≥ 2 was 12.4% in transplant kidneys, which failed more frequently than propensity-matched normal controls (n = 202; P < 0.001). Epidemiological risk factors for early MVI ≥ 2 were delayed graft function, prior AMR, and circulating donor-specific antibodies (DSAs+). Prior recipient sensitization occurred in 72.3%. Early MVI ≥ 2 was classified AMR in 65.3% and cellular rejection in 34.7%, and demonstrated excellent functional recovery and graft survival comparable to normal control kidneys. Late MVI ≥ 2 was predicted by younger (18 = 29 y) age, female recipient, living-donation, prior methylprednisolone, cyclosporine (versus tacrolimus, levels <5 ng/mL), absent antiproliferative therapy, and DSA+ using multivariable epidemiological modeling. Nonadherence caused 49.5%, with iatrogenic minimization responsible for 47.5%, usually for recipient infection. Late MVI ≥ 2 was because of AMR in 93.1%, and characterized by greater interstitial fibrosis, tubular atrophy, complement degradation split-product 4d (C4d) staining of peritubular capillaries+, endothelial C4d staining of glomerular capillaries+, transplant glomerulopathy and vasculopathy scores, DSA strength, and graft failure than early MVI ≥ 2 or normal transplant kidneys. Death-censored graft survival in 149 unique MVI ≥ 2 kidneys was independently determined by nonadherence, serum creatinine, proteinuria, DSA+, Banff C4d staining of peritubular capillaries+, and chronic interstitial fibrosis scores. MVI score and time lost significance using multivariable Cox regression. Conclusions.: The changing expression of MVI ≥ 2 over time is best explained by differences in underimmunosuppression and microvascular injury from AMR impacting allograft function and survival.