Human leukocyte antigen class I antibody-activated endothelium promotes CD206+ M2 macrophage polarization and MMP9 secretion through TLR4 signaling and P-selectin in a model of antibody-mediated rejection and allograft vasculopathy.

HLA donor-specific antibodies (DSA) elicit alloimmune responses against the graft vasculature, leading to endothelial cell (EC) activation and monocyte infiltration during antibody-mediated rejection (AMR). AMR promotes chronic inflammation and remodeling, leading to thickening of the arterial intima termed transplant vasculopathy or cardiac allograft vasculopathy (CAV) in heart transplants. Intragraft-recipient macrophages serve as a diagnostic marker in AMR; however, their polarization and function remain unclear. In this study, we utilized an in vitro Transwell coculture system to explore the mechanisms of monocyte-to-macrophage polarization induced by HLA I DSA-activated ECs. Anti-HLA I (IgG or F(ab')2) antibody-activated ECs induced the polarization of M2 macrophages with increased CD206 expression and MMP9 secretion. However, inhibition of TLR4 signaling or PSGL-1-P-selectin interactions significantly decreased both CD206 and MMP9. Monocyte adherence to Fc-P-selectin coated plates induced M2 macrophages with increased CD206 and MMP9. Moreover, Fc-receptor and IgG interactions synergistically enhanced active-MMP9 in conjunction with P-selectin. Transcriptomic analysis of arteries from DSA+CAV+ rejected cardiac allografts and multiplex-immunofluorescent staining illustrated the expression of CD68+CD206+CD163+MMP9+ M2 macrophages within the neointima of CAV-affected lesions. These findings reveal a novel mechanism linking HLA I antibody-activated endothelium to the generation of M2 macrophages which secrete vascular remodeling proteins contributing to AMR and CAV pathogenesis.

Longitudinal monitoring of Torque Teno virus DNAemia in kidney transplant recipients correlates with long-term complications of inadequate immunosuppression.

Optimization of individual immunosuppression, which reduces the risks of both graft loss and patients' death, is considered the best approach to improve long-term outcomes of renal transplantation. Torque Teno Virus (TTV) DNAemia has emerged as a potential biomarker reflecting the depth of therapeutic immunosuppression during the initial year post-transplantation. However, its efficacy in long-term monitoring remains uncertain. In a cohort study involving 34 stable kidney transplant recipients and 124 healthy volunteers, we established lower and upper TTV DNAemia thresholds (3.75-5.1 log10 cp/mL) correlating with T-cell activatability, antibody response against flu vaccine, and risk for subsequent serious infections or cancer over 50 months. Validation in an independent cohort of 92 recipients confirmed that maintaining TTV DNAemia within this range in >50% of follow-up time points was associated with reduced risks of complications due to inadequate immunosuppression, including de novo DSA, biopsy-proven antibody-mediated rejection, graft loss, infections, or cancer. Multivariate analysis highlighted "in-target" TTV DNAemia as the sole independent variable significantly linked to decreased risk for long-term complications due to inadequate immunosuppression (odds ratio [OR]: 0.27 [0.09-0.77]; p = 0.019). Our data suggest that the longitudinal monitoring of TTV DNAemia in kidney transplant recipients could help preventing the long-term complications due to inadequate immunosuppression.

Pseudomonas aeruginosa infection correlates with high MFI donor-specific antibody development following lung transplantation with consequential graft loss and shortened CLAD-free survival.

BACKGROUND: Donor-specific antibodies (DSAs) are common following lung transplantation (LuTx), yet their role in graft damage is inconclusive. Mean fluorescent intensity (MFI) is the main read-out of DSA diagnostics; however its value is often disregarded when analyzing unwanted post-transplant outcomes such as graft loss or chronic lung allograft dysfunction (CLAD). Here we aim to evaluate an MFI stratification method in these outcomes. METHODS: A cohort of 87 LuTx recipients has been analyzed, in which a cutoff of 8000 MFI has been determined for high MFI based on clinically relevant data. Accordingly, recipients were divided into DSA-negative, DSA-low and DSA-high subgroups. Both graft survival and CLAD-free survival were evaluated. Among factors that may contribute to DSA development we analyzed Pseudomonas aeruginosa (P. aeruginosa) infection in bronchoalveolar lavage (BAL) specimens. RESULTS: High MFI DSAs contributed to clinical antibody-mediated rejection (AMR) and were associated with significantly worse graft (HR: 5.77, p < 0.0001) and CLAD-free survival (HR: 6.47, p = 0.019) compared to low or negative MFI DSA levels. Analysis of BAL specimens revealed a strong correlation between DSA status, P. aeruginosa infection and BAL neutrophilia. DSA-high status and clinical AMR were both independent prognosticators for decreased graft and CLAD-free survival in our multivariate Cox-regression models, whereas BAL neutrophilia was associated with worse graft survival. CONCLUSIONS: P. aeruginosa infection rates are elevated in recipients with a strong DSA response. Our results indicate that the simultaneous interpretation of MFI values and BAL neutrophilia is a feasible approach for risk evaluation and may help clinicians when to initiate DSA desensitization therapy, as early intervention could improve prognosis.

Impact of Transient and Persistent Donor-Specific Antibodies in Lung Transplantation.

Lung transplantation (LuTx) is an established treatment for patients with end-stage lung diseases, however, outcomes are limited by acute and chronic rejection. One aspect that has received increasing attention is the role of the host's humoral alloresponse, particularly the formation of de novo donor-specific antibodies (dnDSAs). The aim of this study was to investigate the clinical significance of transient and persistent dnDSAs and to understand their impact on outcomes after LuTx. A retrospective analysis was conducted using DSA screening data from LuTx recipients obtained at the Medical University of Vienna between February 2016 and March 2021. Of the 405 LuTx recipients analyzed, 205 patients developed dnDSA during the follow-up period. Among these, 167 (81%) had transient dnDSA and 38 (19%) persistent dnDSA. Persistent but not transient dnDSAs were associated with chronic lung allograft dysfunction (CLAD) and antibody-mediated rejection (AMR) (p < 0.001 and p = 0.006, respectively). CLAD-free survival rates for persistent dnDSAs at 1-, 3-, and 5-year post-transplantation were significantly lower than for transient dnDSAs (89%, 59%, 56% vs. 91%, 79%, 77%; p = 0.004). Temporal dynamics of dnDSAs after LuTx have a substantial effect on patient outcomes. This study underlines that the persistence of dnDSAs poses a significant risk to graft and patient survival.

Persistent intracranial steno-occlusion from calcified embolism: a treatment challenge.

INTRODUCTION: Calcified arterial cerebral embolism is a rare occurrence among large and medium vessel occlusions causing ischemic stroke and its diagnosis and treatment is a challenge. The sources of calcified embolism might be a calcific atheroma from the aortic arch and carotid artery, but also heart valve disease has been reported in the literature. Calcified embolism is frequently simultaneous on multiple vascular territories. The prognosis of patients is usually poor, including patients treated by using endovascular thrombectomy (EVT) and this diagnosis could be easily missed in the acute phase. In addition, the optimal secondary prevention has not been yet fully stated. METHODS: We are presenting two cases of acute stroke due to calcified embolism in the middle cerebral artery (MCA) coming from a complicated carotid atheroma, non-stenosing in the first case (a 49 years old man) and stenosing in the second case (a 71 years old man) without clinical indications to intravenous thrombolysis and/or EVT, extensively investigated in the acute phase and followed-up for over 12 months with a favorable clinical course and the persisting steno-occlusion in the involved MCA. In both cases, antiplatelet treatment and targeting of vascular risk factors were done without recurrences in the follow-up period. DISCUSSION: Cerebral calcified embolism has been reported in 5.9% of cases of acute ischemic stroke in a single center series and only in 1.2% of a large retrospective cohort of EVT-treated patients. In both series the prognosis was poor and only one third of EVT-treated patients had functional independence at 3-months follow-up. The natural history of these subtype of ischemic stroke is relatively poorly understood and both etiological diagnosis and treatment have not yet defined. It is possible that some cases might be underdiagnosed and underreported. CONCLUSIONS: Calcified cerebral embolism is a rare cause of stroke, but it is largely underreported and both acute phase and secondary preventive treatment have to be defined.

Intra-aneurysmal contrast agent stasis during intraoperative digital subtraction angiography may predict long-term occlusion after clipping.

PURPOSE: The routine use of intraoperative digital subtraction angiography (iDSA) increases detection of intracranial aneurysm (IA) remnants after microsurgical clipping. Spontaneous thrombosis of IA remnants after clipping is considered a rare phenomenon. We analyse iDSA characteristics to find predictors for IA remnant thrombosis. METHODS: IA with intraoperative detection of a remnant after clipping were identified and divided into remnants experiencing spontaneous thrombosis, and remnants with long-term patency and/or remnant growth. Angiographic features of iDSA were analysed and compared between the two groups. RESULTS: Of 37 IAs with intraoperative remnant on 3D-iDSA, five sustained a spontaneous remnant thrombosis and remained occluded in long-term follow-up. In all five cases, iDSA revealed delayed inflow and consequent stasis of the contrast agent until the late venous phase. On the other hand, in all cases with persistent long-term IA remnants (n = 32) iDSA demonstrated timely arterial contrast inflow and wash-out without stasis of intra-aneurysmal contrast agent. CONCLUSIONS: Contrast stasis in IA remnants during iDSA appears to predict long-term IA occlusion, indicating that clip correction manoeuvres or even attempted endovascular treatment of the remnant IA may be avoided in these patients.

Trans-radial artery microcatheter angiography-assisted juvenile ruptured brainstem arteriovenous malformation resection.

BACKGROUND: Due to their crucial functional location, surgical treatment of brainstem arteriovenous malformations (AVMs) has always been challenging. For unruptured AVMs, we can determine whether radiological therapy, interventional treatment, or surgical resection is feasible based on the AVM structure. However, for ruptured AVMs, microsurgical resection and interventional embolization are effective methods to prevent further rupture. In the microsurgical resection of AVMs, we usually use a hybrid operation to confirm the AVM structure and determine if the AVM is completely resected during the surgery. METHOD: We report a case of juvenile ruptured brainstem AVM resection. The right lateral position and left suboccipital retrosigmoid approach were used. We established an interventional approach via left radial artery and set a microcatheter in the feeding artery. Methylene blue injection via a microcatheter showed the AVM structure, and we totally resected the brainstem AVM under electrophysiological monitoring and navigation. Intraoperative angiography was performed to ensure complete resection without residual nidus. CONCLUSION: This case demonstrates that the trans-radial approach is convenient and safe for special positions in hybrid operations. Methylene blue injection via a microcatheter in the feeding artery provides clearer visualization of the AVM structure under the microscope.

Diagnostic performance of computed tomography-digital subtraction angiography and conventional magnetic resonance imaging for evaluating the vascularity of osseous spinal tumors.

BACKGROUND AND PURPOSE: Patients with hypervascular spinal tumors may have severe blood loss during tumor resection, which increases the risks of perioperative morbidity and mortality. However, the preoperative evaluation of tumor vascularity may be challenging; moreover, the reliability of the data obtained in conventional preoperative noninvasive imaging is debatable. In this study, we compared conventional magnetic resonance imaging (MRI) and subtraction computed tomography angiography (CTA) in terms of their performance in vascularity evaluation. The catheter digital subtraction angiography (DSA) technique was used as a reference standard. METHODS: This study included 123 consecutive patients with spinal tumor who underwent subtraction CTA, catheter DSA, and subsequent surgery between October 2015 and October 2021. Data regarding qualitative and semiquantitative subtraction CTA parameters and conventional MRI signs were collected for comparison with tumor vascularity graded through catheter DSA. The diagnostic performance of qualitative CTA, quantitative CTA, and conventional MRI in assessing spinal tumor vascularity was analyzed. RESULTS: Qualitative subtraction CTA was the best noninvasive imaging modality in terms of diagnostic performance (area under the receiver operating characteristic curve [AUROC], 0.95). Quantitative CTA was relatively inferior (AUROC, 0.87). MRI results had low reliability (AUROC, 0.51 to 0.59). Intratumoral hemorrhage and prominent foraminal venous plexus were found to be the specific signs for hypervascularity (specificity 93.2%). CONCLUSIONS: Qualitative subtraction CTA offers the highest diagnostic value in evaluating spinal tumor vascularity, compared to quantitative CTA and MRI. Although conventional MRI may not be a reliable approach, certain MRI signs may have high specificity, which may be crucial for assessing spinal tumor vascularity.

The effect of lateralization and distalization after Grammont-style reverse total shoulder arthroplasty.

BACKGROUND: The purpose of this study was to evaluate the relationship between multiple radiographic measures of lateralization and distalization and clinical outcome scores after a reverse total shoulder arthroplasty (RTSA). METHODS: We retrospectively evaluated all RTSAs performed by the senior author between January 1, 2007, and November 1, 2017. We then evaluated the visual analog scale for pain (VAS pain), Simple Shoulder Test (SST), and American Shoulder and Elbow Surgeons (ASES) scores and complication and reoperation rates at a minimum of 2-year follow-up. We measured preoperative and postoperative (2-week) radiographs for the lateralization shoulder angle (LSA), the distalization shoulder angle (DSA), lateral humeral offset, and the distance from the glenoid to the lateral aspect of the greater tuberosity. A multivariable analysis was performed to evaluate the effect of the postoperative radiographic measurements on final patient-reported outcomes (ASES scores, SST, and VAS pain). RESULTS: The cohort included 216 shoulders from unique patients who had patient-reported outcome scores available at a minimum of 2-year follow-up (average, 4.0 ± 1.9 years) for a total follow-up rate of 70%. In the multivariable models, more lateralization (LSA) was associated with worse final ASES scores -0.52 (95% confidence interval [CI]: -0.88, -0.17; P = .004), and more distalization (DSA) was associated with better final ASES scores 0.40 (95% CI: 0.11, 0.69; P = .007). More lateralization (LSA) was associated with worse final SST scores -0.06 (95% CI: -0.11, -0.003; P = .039). Finally, greater distalization (DSA) was associated with lower final VAS pain scores, ratio = 0.98 (95% CI: 0.96, 1.00; P = .021). CONCLUSIONS: Greater distalization and less lateralization are associated with better function and less pain after a Grammont-style RTSA. When using a Grammont-style implant, remaining consistent with Grammont's principles of implant placement will afford better final clinical outcomes.

Can we separately measure glenoid vs. humeral lateralization and distalization in reverse shoulder arthroplasty?

BACKGROUND: Lateralization and distalization in reverse shoulder arthroplasty (RSA) can be measured on anteroposterior (AP) radiographs using 2 previously described angles: lateralization shoulder angle (LSA) and distalization shoulder angle (DSA). However, these 2 angles measure global lateralization and distalization but do not allow to differentiate how much lateralization or distalization are attributable to the glenoid and the humerus. We hypothesized that new angles could allow us to separately measure glenoid vs. humeral lateralization and distalization. A more precise understanding of independent glenoid and humeral contributions to lateralization and distalization may be beneficial in subsequent clinical research. METHOD: Retrospective analysis of postoperative AP radiographs of 100 patients who underwent primary RSA for cuff-tear arthropathy, massive cuff tear, or glenohumeral osteoarthritis were analyzed. The new angles that we proposed use well-known bony landmarks (the acromion, glenoid, and humerus) and the most lateral point of the glenosphere, which we termed the "glenoid pivot point" (GPP). For lateralization, we used the GPP to split LSA into 2 new angles: glenoid lateralization angle (GLA) and humeral lateralization angle (HLA). For distalization, we introduced the modified distalization shoulder angle (mDSA) that can also be split into 2 new angles: glenoid distalization angle (GDA) and humeral distalization angle (HDA). Three orthopedic surgeons measured the new angles, using the online tool Tyche. Mean values with overall and individual standard deviations as well as intraclass correlation coefficients (ICCs) were calculated. RESULTS: Because the angles form a triangle, the following equations can be made: LSA = GLA + HLA, and mDSA = GDA + HDA. All angles showed excellent inter- and intraobserver reliability (ICC = 0.92-0.97) with low means of individual standard deviations that indicate a precision of 2° for each angle. CONCLUSION: Use of the most lateral part of the glenosphere (termed glenoid pivot point) allows us to separately measure glenoid vs. humeral lateralization and distalization. The 4 new angles (HLA, GLA, GDA, HDA) described in the present study can be used on true AP radiographs, routinely obtained after shoulder replacement, and the measured angles may be used with all types of reverse prostheses available.

Imaging review of spontaneous renal hemorrhage.

Spontaneous renal hemorrhage (SRH) is a diagnostic challenge and a significant cause of morbidity, and sometimes mortality. Early identification is essential to institute lifesaving and reno-protective interventions. In this review, we classify spontaneous renal hemorrhage by location, presentation and etiology. We also discuss the diagnostic approach to renal hemorrhage and optimum imaging modalities to arrive at the diagnosis. Finally, we review strategies to avoid missing a diagnosis of SRH and discuss the pitfalls of imaging in the presence of renal hemorrhage.

A Novel Control Strategy for Soft Open Point to Address Terminal Voltage Violations and Load Rate Imbalance in Low-Voltage Power Distribution Station Areas.

In low-voltage power distribution station areas (DSAs), sensor devices and communication networks are often inadequate. Therefore, the control strategies mainly used for soft open points (SOPs) based on global information in medium-voltage distribution networks are difficult to be directly applied to low-voltage DSAs. This paper proposes a novel control strategy for SOP that only requires collecting the local information of SOP and the load rate of transformers. It aims to address the issues faced of voltage violations at the end of feeders and the load rate imbalance among adjacent DSAs under the current high penetration of renewable energy sources. In this paper, first, a sensor network consisting of sensor devices located at the transformers and each port of the SOP is introduced for information collection. Then, based on the sensitivity relationship between the node voltage and the injected power, considering capacity and voltage safety constraints, the adjustable range of the active power output for each port of the SOP is derived. According to this range, the operating states of the DSAs are categorized into four scenarios. For each scenario, the adjustment amount of SOP output power is determined to achieve comprehensive regulation of terminal voltage and load rate of all DSAs interconnected by SOP. Finally, the effectiveness of the proposed strategy is verified based on a simulation model of three flexible interconnected DSAs established in MATLAB/Simulink.

The lateralization and distalization index is more reliable than angular radiographic measurements in reverse shoulder arthroplasty.

BACKGROUND: The lateralization shoulder angle (LSA) and distalization shoulder angle (DSA) are used to reproducibly measure lateralization and distalization after reverse shoulder arthroplasty (RSA). However, LSA and DSA may not offer a precise measurement of humeral lateralization and distalization and this relationship has not been explored. The aim of this study was to evaluate the validity of these measurements and to propose new measurement methods to estimate implant lateralization and distalization. METHODS: 3D models were constructed from computed tomography (CT) scans of 30 patients using a software platform. For each patient 24 different RSA modifications were created, resulting in 720 different RSA configurations. For each configuration LSA and DSA angles as well as lateralization and distalization distances were measured. Moreover, for each configuration two new measurements were done: the lateralization index (LI) and distalization index (DI). Correlations of the lateralization and distalization parameters were evaluated between measurements. RESULTS: Weak correlations were founded between LSA and lateralization (r = 0.36, p < 0.01), whereas moderate correlations were observed between LI and lateralization (r = 0.72, p < 0.01). No significant correlations were found between DSA and distalization (r = 0.17, p = 0.113). In contrast, moderate correlations were identified between DI and distalization (r = 0.69, p < 0.01). CONCLUSION: LI and DI are more reliable methods to estimate implant lateralization and distalization compared to angular radiographic measurements. However, the prognostic significance in predicting clinical outcomes after RSA remains unknown.

Case Study of a Complex Neurovascular Disorder: Choroidal Arteriovenous Malformation.

This study conducts an in-depth analysis of the management of a complex arteriovenous malformation (AVM) in a 44-year-old individual, who initially manifested with acute left hemiparesis and progressively declined into a comatose state. Diagnostic neuroimaging identified a substantial right fronto-temporal intraparenchymal hematoma via a CT scan. Cerebral angiography further elucidated a choroidal AVM originating from the anterior choroidal artery, accompanied by intranidal aneurysms. The elected treatment strategy was the surgical excision of the AVM. The procedure achieved complete removal of the intracranial AVM, situated in a neurologically sensitive region, leading to notable neurological recovery. This study thoroughly explores and critically evaluates a wide spectrum of treatment approaches for intracranial arteriovenous malformations, including novel endovascular therapies. Despite extensive discourse on AVM in contemporary literature, this report is among the few documenting the treatment of a choroidal AVM via a microsurgical technique, and highlights various therapeutic options.

Effects of invivo CXCR4 blockade and proteasome inhibition on bone marrow plasma cells in HLA-sensitized kidney transplant candidates.

To date, plasma cell (PC)-targeted therapies have been limited by suboptimal PC depletion and antibody rebound. We hypothesized this is partly because of PC residence in protective bone marrow (BM) microenvironments. The purpose of this proof-of-concept study was to examine the effects of the CXCR4 antagonist, plerixafor, on PC BM residence; its safety profile (alone and in combination with a proteasome inhibitor, bortezomib); and the transcriptional effect on BMPCs in HLA-sensitized kidney transplant candidates. Participants were enrolled into 3 groups: group A (n = 4), plerixafor monotherapy; and groups B (n = 4) and C (n = 4), plerixafor and bortezomib combinations. CD34+ stem cell and PC levels increased in the blood after plerixafor treatment. PC recovery from BM aspirates varied depending on the dose of plerixafor and bortezomib. Single-cell RNA sequencing on BMPCs from 3 group C participants pretreatment and posttreatment revealed multiple populations of PCs, with a posttreatment enrichment of oxidative phosphorylation, proteasome assembly, cytoplasmic translation, and autophagy-related genes. Murine studies demonstrated dually inhibiting the proteasome and autophagy resulted in greater BMPC death than did monotherapies. In conclusion, this pilot study revealed anticipated effects of combined plerixafor and bortezomib on BMPCs, an acceptable safety profile, and suggests the potential for autophagy inhibitors in desensitization regimens.

Deceased-Donor Acute Kidney Injury and Acute Rejection in Kidney Transplant Recipients: A Multicenter Cohort.

RATIONALE & OBJECTIVE: Donor acute kidney injury (AKI) activates innate immunity, enhances HLA expression in the kidney allograft, and provokes recipient alloimmune responses. We hypothesized that injury and inflammation that manifested in deceased-donor urine biomarkers would be associated with higher rates of biopsy-proven acute rejection (BPAR) and allograft failure after transplantation. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: 862 deceased donors for 1,137 kidney recipients at 13 centers. EXPOSURES: We measured concentrations of interleukin 18 (IL-18), kidney injury molecule 1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) in deceased donor urine. We also used the Acute Kidney Injury Network (AKIN) criteria to assess donor clinical AKI. OUTCOMES: The primary outcome was a composite of BPAR and graft failure (not from death). A secondary outcome was the composite of BPAR, graft failure, and/or de novo donor-specific antibody (DSA). Outcomes were ascertained in the first posttransplant year. ANALYTICAL APPROACH: Multivariable Fine-Gray models with death as a competing risk. RESULTS: Mean recipient age was 54 ± 13 (SD) years, and 82% received antithymocyte globulin. We found no significant associations between donor urinary IL-18, KIM-1, and NGAL and the primary outcome (subdistribution hazard ratio [HR] for highest vs lowest tertile of 0.76 [95% CI, 0.45-1.28], 1.20 [95% CI, 0.69-2.07], and 1.14 [95% CI, 0.71-1.84], respectively). In secondary analyses, we detected no significant associations between clinically defined AKI and the primary outcome or between donor biomarkers and the composite outcome of BPAR, graft failure, and/or de novo DSA. LIMITATIONS: BPAR was ascertained through for-cause biopsies, not surveillance biopsies. CONCLUSIONS: In a large cohort of kidney recipients who almost all received induction with thymoglobulin, donor injury biomarkers were associated with neither graft failure and rejection nor a secondary outcome that included de novo DSA. These findings provide some reassurance that centers can successfully manage immunological complications using deceased-donor kidneys with AKI.

Impact of pre-transplant donor specific antibodies detected by Luminex with negative microlymphocytotoxicity assay and flow crossmatch in live-related renal transplant recipients.

INTRODUCTION/AIM: The Luminex assay, where beads are coated with a single HLA antigen, has been shown to detect HLA antibodies with more sensitivity and specificity as compared to microlymphocytotoxicity (CDC) assay and flow cross match (FCXM). We report the impact of low Mean Flourescence intensity (MFI) pre-transplant DSA by Luminex with negative CDC and FCXM on acute rejection, graft function, and survival. METHODS: In this retrospective study between January 2015 to December 2021, 45 recipients had pre-transplant anti-HLA donor-specific antibodies (DSAs) detected by Luminex. Two control groups of 45 patients each matched for age and gender, first with non-DSA HLA antibodies and second with no antibodies by Luminex were selected to compare outcomes with DSA group. RESULTS: In the DSA group of 45, 22 (48.8%) had class I (MFI mean 4043 ± 1909, range: 1096-7111), 20 (44.4%) class II (MFI mean 3601 ± 2310, range: 1031-9259), and 3 (6.6%) both class I (MFI mean 4746 ± 1922) and class II (MFI mean 3940 ± 2312) antibodies. Acute rejection episodes were reported in 15.6%, DSA group, 17.8% in non-DSA, and 24.4% in no antibody group (p = .538). Death censored graft survival at 1 and 5 years was 98% and 93% in DSA group, 100% and 95% in non-DSA and 93% and 85% in the no antibody group (p = .254). CONCLUSIONS: Patients with low MFI DSA pre-transplant, with a negative CDC and FCXM under ATG induction, have similar graft outcomes at 1 and 5 years when compared to non-DSA and no antibody groups.

Tocilizumab for treatment of chronic active antibody-mediated rejection in kidney transplant recipients.

BACKGROUND: The optimal treatment for chronic active antibody-mediated rejection (ca-AMR) remains unclear. Tocilizumab (TCZ), a monoclonal antibody against IL-6, has been proposed as a therapeutic option. We reported our experience treating ca-AMR with TCZ either as the first line option or as a rescue therapy. METHODS: We studied 11 adult kidney transplant recipients with biopsy-proven ca-AMR and preserved kidney function (eGFR 57 ± 18) who were treated with TCZ (8 mg/kg IV monthly). All biopsies were prompted by abnormal surveillance biomarker testing with DSA and/or dd-cfDNA. Clinical monitoring included dd-cfDNA and DSA testing every 3 months during the treatment with TCZ. RESULTS: In this cohort, ca-AMR was diagnosed at a median of 90 months (range 14-224) post-transplant, and 4 of 11 patients had DSA negative ca-AMR. Patients received a minimum of 3 months of TCZ, with 6 patients receiving at least 12 months of TCZ. Dd-cfDNA was elevated in all patients, with a median 2.24% at the start of TCZ treatment. After 6 months of TCZ treatment, 8/11 patients had dd- cfDNA <1%, and 3/11 had values <0.5%. Among those who completed at least 12 months of TCZ, dd-cfDNA decreased by 29% at 6 months (p = .05) and 47% by 12 months (p = .04). DSA also stabilized and, by 12 months, was reduced by 29% (p = .047). Graft function remained stable with no graft loss during treatment. There was a nonsignificant trend towards proteinuria reduction. During the course of treatment with tocilizumab, two patients experienced moderate to severe infections. CONCLUSIONS: In our early short-term experience, TCZ appears to reduce graft injury as measured by dd-cfDNA and modulate the immune response as evident by a modest reduction in immunodominant DSA MFI. Allograft function and proteinuria also stabilized.

Donor specific antibodies association with survival and adverse events after heart transplantation: A single center retrospective study between 2006 and 2021.

OBJECTIVE: Newly detected donor HLA-specific antibodies (DSA) are historically known to be associated with reduced survival in heart transplant patients. Our objective is to clarify the modern incidence of DSA and determine its relationship with survival and MACE. METHODS: This retrospective study included all patients undergoing orthotopic heart transplantation at Harefield Hospital, London between January 1, 2006 and May 31, 2021. We identified patients who developed DSA at any point post heart transplantation and its effect on survival and MACE (defined as rejection, coronary event, stroke, and arrhythmia. RESULTS: In total of 232 patients were included with a median follow up time of 4.7 years post heart transplantation. 23.7% of patients included developed DSA post heart transplantation. There was a significantly increased risk of death in patients developing DSA versus not (sub distribution hazard ratio [SHR] 1.83, 95% confidence interval 1.03-3.24, p = .04). At the time of detection of DSA, 38.2% of the cohort had rejection necessitating treatment. A MACE event had occurred in 48.1% by 2 years and 53.7% by 3 years in the DSA cohort. There was a significantly increased risk of MACE in patients developing DSA versus not (SHR 2.48 [1.58-3.89, p < .0001]). CONCLUSIONS: This study showed an increased risk of death and MACE in patients developing DSA post heart transplantation. Further research is required into the optimal management of these patients.

Morphologic and immunophenotypic evaluation of liver allograft biopsies with contemporaneous serum DSA measurements.

BACKGROUND: Acute antibody mediated rejection is increasingly identified in liver allografts as a unique form of alloimmune injury associated with donor specific antibodies (DSA). This manifests pathologically as microvascular injury and C4d uptake. Despite the liver allograft's relative resistance to alloimmune injury, liver allografts are not impervious to cellular and antibody-mediated rejection. METHODS: In this blinded control study, we evaluated CD163 immunohistochemistry and applied the Banff 2016 criteria for diagnosis of acute AMR on a group of indication allograft liver biopsies from DSA positive patients and compared them to indication biopsies from DSA negative controls. RESULTS: Most DSA positive patients were females (75%, p = .027), and underwent transplantation for HCV infection. Significant histopathological predictors of serum DSA positivity were Banff H-score (p = .01), moderate to severe cholestasis (p = .03), and CD163 score > 2 (p = .029). Other morphologic features that showed a trend with DSA positivity include Banff portal C4d-score (p = .06), bile ductular reaction (p = .07), and central perivenulitis (p = .07). The odds of DSA sMFI ≥5000 was 12.5 times higher in those with a C4d score >1 than those with a C4d score ≤ 1 (p = .04). Incidence of definite for aAMR in the DSA positive cohort was 25% (n = 5), and 0% in the DSA negative cohort. A group of 5 DSA positive cases were not classifiable by the current scheme. CONCLUSION: Sinusoidal CD163, Banff H-score, and diffuse C4d are predictors of serum DSA, and facilitate recognition of histopathological features associated with serum DSA and tissue-antibody interaction.