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Solid organ transplantation remains the life-saving treatment for end-stage organ failure, but chronic rejection remains a major obstacle to long-term allograft outcomes and has not improved substantially. Tertiary lymphoid organs (TLOs) are ectopic lymphoid structures that form under conditions of chronic inflammation, and evidence from human transplantation suggests that TLOs regularly form in allografts undergoing chronic rejection. In this study, we utilized a mouse renal transplantation model and manipulation of the lymphotoxin αβ/lymphotoxin β receptor (LTαβ/LTβR) pathway, which is essential for TLO formation, to define the role of TLOs in transplantation. We showed that intragraft TLOs are sufficient to activate the alloimmune response and mediate graft rejection in a model where the only lymphoid organs are TLOs in the allograft. When transplanted to recipients with a normal set of secondary lymphoid organs, the presence of graft TLOs or LTα overexpression accelerated rejection. If the LTβR pathway was disrupted in the donor graft, TLO formation was abrogated, and graft survival was prolonged. Intravital microscopy of renal TLOs demonstrated that local T and B cell activation in TLOs is similar to that observed in secondary lymphoid organs. In summary, we demonstrated that immune activation in TLOs contributes to local immune responses, leading to earlier allograft failure. TLOs and the LTαβ/LTβR pathway are therefore prime targets to limit local immune responses and prevent allograft rejection. These findings are applicable to other diseases, such as autoimmune diseases or tumors, where either limiting or boosting local immune responses is beneficial and improves disease outcomes.

BK polyomavirus (BKV or BKPyV) associated nephropathy affects up to 10% of kidney transplant recipients (KTRs). BKV isolates are categorized into four genotypes. It is currently unclear whether the four genotypes are also serotypes. To address this issue, we developed high-throughput serological assays based on antibody-mediated neutralization of BKV genotype I and IV reporter vectors (pseudoviruses). Neutralization-based testing of sera from mice immunized with BKV-I or BKV-IV virus-like particles (VLPs) or sera from naturally infected human subjects revealed that BKV-I specific serum antibodies are poorly neutralizing against BKV-IV and vice versa. The fact that BKV-I and BKV-IV are distinct serotypes was less evident in traditional VLP-based ELISAs. BKV-I and BKV-IV neutralization assays were used to examine BKV type-specific neutralizing antibody responses in KTRs at various time points after transplantation. At study entry, sera from 5% and 49% of KTRs showed no detectable neutralizing activity for BKV-I or BKV-IV neutralization, respectively. By one year after transplantation, all KTRs were neutralization seropositive for BKV-I, and 43% of the initially BKV-IV seronegative subjects showed evidence of acute seroconversion for BKV-IV neutralization. The results suggest a model in which BKV-IV-specific seroconversion reflects a de novo BKV-IV infection in KTRs who initially lack protective antibody responses capable of neutralizing genotype IV BKVs. If this model is correct, it suggests that pre-vaccinating prospective KTRs with a multivalent VLP-based vaccine against all BKV serotypes, or administration of BKV-neutralizing antibodies, might offer protection against graft loss or dysfunction due to BKV associated nephropathy.

Abstract Objectives Pathologists interpreting kidney allograft biopsies using the Banff system usually start by recording component scores (eg, i, t, cg) using histopathologic criteria committed to memory. Component scores are then melded into diagnoses using the same manual/mental processes. This approach to complex Banff rules during routine sign-out produces a lack of fidelity and needs improvement. Methods We constructed a web-based “smart template” (software-assisted sign-out) system that uniquely starts with upstream Banff-defined additional diagnostic parameters (eg, infection) and histopathologic criteria (eg, percent interstitial inflammation) collectively referred to as feeder data that is then translated into component scores and integrated into final diagnoses using software-encoded decision trees. Results Software-assisted sign-out enables pathologists to (1) accurately and uniformly apply Banff rules, thereby eliminating human inconsistencies (present in 25% of the cohort); (2) document areas of improvement; (3) show improved correlation with function; (4) examine t-Distributed Stochastic Neighbor Embedding clustering for diagnosis stratification; and (5) ready upstream incorporation of artificial intelligence–assisted scoring of biopsies. Conclusions Compared with the legacy approach, software-assisted sign-out improves Banff accuracy and fidelity, more closely correlates with kidney function, is practical for routine clinical work and translational research studies, facilitates downstream integration with nonpathology data, and readies biopsy scoring for artificial intelligence algorithms.

Polyomavirus type BK (BK virus) is a nonenveloped virus with circular, double-stranded DNA that has 70 percent homology with simian virus 40. It was first recognized as a member of the polyomavirus family in 1971, after isolation from the urine of a renal-transplant recipient with ureteral stenosis. 1 , 2 Subsequent studies documented a worldwide rate of seroprevalence in adults of 60 to 80 percent, with first infections usually occurring in childhood by the respiratory route, followed by latency of the virus in the urogenital tract. Among renal-transplant recipients who are receiving immunosuppressive therapy, 10 to 60 percent have reactivation of polyomavirus . . .

Lymphocytic tubulitis is a well-accepted criterion for acute cellular rejection in renal allograft biopsies. Neutrophilic tubulitis has been used as a surrogate marker for urinary tract infection, but it is not clear how reliably this lesion can be used to make this diagnosis. Biopsy findings were correlated with clinical features in 26 renal allograft biopsies with interstitial polymorphonuclear infiltrates associated with neutrophilic tubulitis. The grade of neutrophilic tubulitis exceeded the grade of lymphocytic tubulitis in 7 (44%) of 16 patients with, but in only 0 patients without, a positive urine culture. Culture confirmed urinary tract infection in 16 (62%) of 26 patients. It is possible that prior antibiotic therapy led to a false-negative culture and masked the diagnosis in two additional patients. Lymphocytic tubulitis made it difficult to exclude concurrent acute cellular rejection in all biopsies studied. In 6 (23%) of 26 patients, negative cultures and response to steroid treatment confirmed that neutrophilic tubulitis can occur in biopsies without urinary tract infection. The relative contributions of infection and rejection could not be determined in patients treated with both steroids and antibiotics. Neutrophilic tubulitis in a renal allograft biopsy should alert the clinician to the possibility of urinary tract infection, even if concurrent lymphocytic tubulitis is present. Confirmation by urine culture is needed because biopsies with ischemic injury and acute cellular or antibody-mediated rejection can show overlapping histology.

POST-TRANSPLANTATION lymphoproliferative disease (PTLD), either polyclonal or monoclonal, complicates the clinical course of 1 to 10 percent of organ-transplant recipients. 1 2 3 Immunohistochemical studies have demonstrated that the lymphoid cells within the lesions of PTLD almost invariably contain Epstein–Barr virus (EBV), primarily in a state of latent infection. 4 , 5 The EBER-1 gene is expressed early during latent EBV infection and codes for a small messenger RNA (mRNA) expressed at up to 10 7 copies per cell. 6 We and others have previously demonstrated the value of the detection of EBER-1 RNA for identifying EBV-infected cells in formalin-fixed paraffin-embedded tissues. 7 , 8 In the current investigation, we used . . .

Building upon a foundational Human Kidney resource, we present a comprehensive multi-modal atlas that defines spatially resolved versus unresolved repair states and mechanisms in human kidney disease. Homeostatic interactions between injured kidney epithelium and its surrounding milieu determine successful repair outcomes, while pathogenic signaling promotes unresolved inflammation and fibrosis leading to chronic disease. We integrated multiple single-cell and spatial modalities across ~700 samples from >350 patients (~250 research biopsies), analyzing ~1.7 million cells alongside complementary mouse multi-omic profiles spanning acute-to-chronic injury and aging (>300,000 cells) and spatial transcriptomic analysis of >150 human biopsies. This cross-species atlas delineates functional pathways and druggable targets across the nephron and defines gene regulatory networks and chromatin landscapes governing tubular, fibroblast, and immune cell transitions from injury to either recovery or failed repair states. We identified distinct cellular states associated with specific pathological features that show dynamic distributions between acute kidney injury (AKI) and chronic kidney disease (CKD), organized within unique spatial niches that reveal progression mechanisms from early injury to unresolved disease. Gene regulatory analyses prioritized key transcription factor activities (SOX4, SOX9, NFKB1, REL, KLFs) and their target networks establishing disease states and tissue microenvironments. These regulatory programs were directly linked to clinical outcomes, identifying molecular signatures of recovery and secreted biomarkers predictive of AKI-to-CKD progression, providing a key resource for therapeutic development and precision medicine approaches in kidney disease.

Randhawa argues that a recent study by Nickeleit et al indicates that BK virus nephropathy in allograft recipients is becoming recognized as an important clinical problem and that molecular diagnostic testing will be a useful method for identifying and following patients who are at risk and those who are already affected.