Cornell, Lynn D.

Objective To quantitatively examine immune cell markers and spatial distribution in human diabetic kidney disease (DKD) to enhance understanding of the inflammatory landscape contributing to injury. Maladaptive inflammation is an underrecognized contributor to DKD pathogenesis and progression and remains undertreated. Patients and methods NanoString GeoMx™ Digital Spatial Profiling technology targeted antibodies labeled with unique oligonucleotide barcode in kidney biopsy [DKD (n=5), tubulointerstitial nephritis (TIN; n=4), and normal (n=2)] with regions of interest selection of compartments (glomeruli, tubules, interstitium). Inflammation-related proteins were analyzed with differential expression through linear mixed modeling. Results Compared to normal tissue, inflammatory cell surface protein markers were increased in DKD tubules and interstitium. Markers of T cells (CD4, CD44), macrophages (CD68; proinflammatory), and antigen-presenting cells (APCs; CD40 and CD11c) were increased across all DKD compartments (vs. normal). Macrophage (CD163; prorepair) marker was increased in DKD tubules and interstitium (vs. normal). Fewer differences were observed in glomeruli for normal vs. DKD or TIN vs. DKD groups. CD66b+ (granulocytes) cell marker was higher in DKD (vs. TIN). As expected, TIN had higher levels of T cell and macrophage markers in tubules and interstitium (vs. DKD). Interestingly, CD34, a hematopoietic stem cell and endothelial cell marker, was lower in DKD tubules and interstitium (vs. normal) but higher in DKD (vs. TIN). Conclusion NanoString GeoMx DSP technology may fulfil a role in enhancing the understanding the inflammatory landscape engaged in DKD pathogenesis as well as measuring response to therapy. Moreover, additional investigations of CD34 progenitor cell depletion in DKD may be warranted.

ABSTRACTIntroductionThe diagnosis of antibody‐mediated rejection (AMR) requires input from several transplant professionals. Bringing clinical and laboratory experts together may help standardize care. Yet, little is known about current global practices of multidisciplinary meetings for AMR management.MethodsThe Banff Antibody‐Mediated Injury Working Group approached professional societies worldwide to distribute a survey on the availability, content, participants, perceived value, and barriers to the implementation of multidisciplinary meetings.ResultsFour hundred two transplant professionals from six continents caring for kidney (90.55%), liver (21.14%), pancreas (20.65%), heart (15.17%), and lung (14.18%) transplant recipients participated in the survey, and 302 (75.12%) reported attending multidisciplinary meetings. Multidisciplinary meetings were more prevalent in academic centers, in high‐ versus low‐to‐middle‐income regions (81.03% and 65.99%, respectively; p < 0.001), and in mid‐to‐large size transplant programs compared to smaller programs. Perceived value included continued professional development (97.68%) and trainee education (95.70%). AMR was reported to be discussed at these meetings by 217 respondents with case presentations reviewing patient characteristics, histology, and HLA antibody data. A third of the respondents reviewed non‐HLA/pathogenic autoantibodies and/or molecular diagnostics, with the latter being more frequently applied in high‐ versus low‐to‐middle‐income regions (46.71% and 12.31%, respectively; p < 0.001). AMR case presentations allowed diagnosis revision, actionable management plans and were perceived as improving care. The primary barrier to the implementation of multidisciplinary meetings (63.27%) was the unavailability of transplant professionals (e.g., transplant immunologists).ConclusionFacilitating multidisciplinary meetings through the remote participation of pertinent experts and incentivizing participation through remuneration, protected time, or continued medical education may help standardize AMR diagnosis and harmonize its management.

Abstract Objectives Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is an autoinflammatory disease caused by somatic mutation of UBA1 and affects multiple organ systems. Involvement of the kidneys is not well characterized. We aimed to investigate the incidence, risk factors and histopathologic features of acute kidney injury (AKI) in VEXAS syndrome. Methods Patients with genetically confirmed UBA1 mutation consistent with VEXAS were included. Charts were manually reviewed. Cox regression analysis was used to identify variables associated with time-to-first AKI event. For patients with a kidney biopsy, histopathologic findings were reviewed. Results Eighty-one patients were included, all white men, with a mean age of 66.3 ± 8.6 years. Median (IQR) follow up was 3.5 (2.1–5.2) years during which 20 (25%) developed AKI and 22% died. AKI relapsed in 90% of cases for a median of 6 times during the follow up period. Cumulative incidence estimates (95% CI) for AKI at 1, 3 and 5 years were 6.2% (0.80–11.3%), 16.7% (7.5–25.0%) and 27.9% (14.9–38.9%), respectively. Age and baseline C-reactive protein (CRP) were significantly associated with time-to-first AKI event. Six patients underwent a kidney biopsy. Findings included, plasma cell-rich interstitial nephritis (n = 3), neutrophilic-rich interstitial inflammation (n = 1), leukocytoclastic peritubular capillaritis (n = 1) and acute tubular injury (n = 1). AKI responded well to treatment with glucocorticoids but had relapse upon tapering. Conclusion AKI is an underrecognized feature of VEXAS occurring in 25% of patients in this cohort. Age at diagnosis and CRP were associated with time to first AKI event during follow up. Plasma cell-rich interstitial nephritis was the most common histopathologic finding.

In September 2022, in Banff, Alberta, Canada, the XVIth Banff meeting, corresponding to the 30th anniversary of the Banff classification, was held, leading to 2 recent publications. Discussions at the Banff meeting focused on proposing improvements to the Banff process as a whole. In line with this, a unique opportunity was offered to a selected group of 16 representatives from the pathology and transplant nephrology community, experts in the field of kidney transplantation, to review these 2 Banff manuscripts. The aim was to provide an insightful commentary, to gauge any prospective influence the proposed changes may have, and to identify any potential areas for future enhancement within the Banff classification. The group expressed its satisfaction with the incorporation of 2 new entities, namely “microvascular inflammation/injury donor-specific antibodies–negative and C4d negative” and “probable antibody-mediated rejection,” into category 2. These changes expand the classification, facilitating the capture of more biopsies and providing an opportunity to explore the clinical implications of these lesions further. However, we found that the Banff classification remains complex, potentially hindering its widespread utilization, even if a degree of complexity may be unavoidable given the intricate pathophysiology of kidney allograft pathology. Addressing the histomorphologic diagnosis of chronic active T cell–mediated rejection (CA TCMR), potentially reconsidering a diagnostic-agnostic approach, as for category 2, to inflammation in interstitial fibrosis and tubular atrophy and chronic active T cell–mediated rejection was also an important objective. Furthermore, we felt a need for more evidence before molecular diagnostics could be routinely integrated and emphasized the need for clinical and histologic context determination and the substantiation of its clinical impact through rigorous clinical trials. Finally, our discussions stressed the ongoing necessity for multidisciplinary decision-making regarding patient care.