The spectrum of histological findings in transplanted kidneys from HIV-positive donors to HIV-positive recipients is relatively unexplored. This study describes the type and timing of histological diagnoses observed in this unique cohort.

Adequate biopsies were analyzed at implantation and posttransplant between September 2008 and May 2022. Histological disease spectrum, distributions over time, and relevant clinical characteristics and management were reported for both for-cause and protocol biopsies.

Twenty-four implantation biopsies from 31 deceased donors and 179 allograft biopsies (100 for-cause, 79 protocol) from 50 recipients were analyzed. Most rejection episodes occurred in the first year posttransplant. Eighteen recipients (36%) had at least 1 episode of biopsy-confirmed acute/chronic T cell-mediated rejection (TCMR) or active antibody-mediated rejection (AMR). Protocol biopsies showed no active AMR or acute/chronic TCMR. However, 9 of 79 biopsies identified borderline/suspicious TCMR. Common nonrejection diagnoses were interstitial fibrosis and tubular atrophy, ascending pyelonephritis, and calcineurin inhibitor toxicity. Classic and suspected HIV-associated nephropathy (HIVAN) were identified in 3 and 6 patients, respectively. Protocol biopsies diagnosed 1 case of classic HIVAN and 6 cases of suspected HIVAN. AMR most adversely affected kidney function and significantly contributed to graft failure.

The histological findings in this cohort of HIV-positive kidney transplant recipients who received grafts from unmatched HIV-positive donors revealed a spectrum of abnormalities. Protocol biopsies added to surveillance on borderline rejection and assisted in the recognition of HIVAN. Confirmed rejection occurred in 18 recipients (36%). Understanding the factors contributing to this may assist in the optimization of immunosuppressive protocols in the future.

Peripheral blood biomarkers aim to noninvasively diagnose kidney allograft rejection, but most lack robust independent validation. TruGraf is intended to exclude subclinical cellular rejection (TCMR), whereas donor-derived cell-free DNA Viracor-TRAC has proven value in excluding antibody-mediated rejection (AMR). We aim to validate both biomarkers for accurate rejection diagnosis in a real-world clinical setting.

We prospectively included 230 unselected, consecutive kidney transplants from 6 centers undergoing for-cause and protocol biopsies with paired blood samples from December 2021 to 2022. TruGraf and Viracor-TRAC were blindly run by a central laboratory.

The incidence of rejection was 22.6% (17.3% surveillance; 27% for-cause biopsies). Inflammation was associated with higher TRAC levels, with AMR/mixed and microvascular inflammation (MVI) showing the highest levels ( P  < 0.05). TruGraf did not associate with any specific allograft injury. No biomarkers, individually or combined, accurately diagnosed any rejection (area under the receiver operating characteristic curve [AUROC] < 0.65). However, high TRAC levels, when combined with DSA in for-cause biopsies, predicted AMR/mixed rejection or MVI (AUROC = 0.817; P  < 0.001), outperforming serum creatinine and DSA (AUROC < 0.65).

In this large, prospective, observational real-life study, we were unable to validate TruGraf and TRAC to diagnose rejection but found a useful context of use for TRAC to noninvasively diagnose AMR/mixed or MVI in conjunction with DSA in dysfunctioning graft.

Therapeutic drug monitoring of immunosuppressants is critical in balancing insufficient immunosuppression due to underdosing, and severe adverse effects due to overdosage. For a more comprehensive therapeutic drug monitoring and follow-up of transplant patients, the aim was to develop a liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of tacrolimus, cyclosporine A, tryptophan, kynurenine, and creatinine using a volumetric absorptive microsampling device.

Venous and capillary blood samples were simultaneously collected using a volumetric absorptive microsampling device called Mitra. The method involved protein precipitation followed by offline solid-phase extraction using a positive pressure manifold. Chromatographic separation was achieved by a formic acid-ammonium formate-methanol gradient on a Synergi Polar reversed-phase column. Multiple reaction monitoring in the positive ion mode and stable isotope-labeled internal standards were used for quantification. Validation was performed according to the European Medicines Agency and US Food and Drug Administration (FDA) guidelines.

Validation was successful, meeting European Medicines Agency and FDA guidelines. Investigation of selectivity, accuracy, and precision met the required criteria of a deviation <15%. Internal standards successfully compensated potential matrix effects. A comparison of 26 anonymized samples from transplant patients on Mitra with venous blood controls demonstrated the method's suitability.

For the first time, we herein describe a liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of tacrolimus, cyclosporine A, tryptophan, kynurenine, and creatinine on Mitra. Self-collection of samples may facilitate therapeutic monitoring. Simultaneous determination of creatinine may help monitor kidney function, while tryptophan and kynurenine may serve as a biomarker for early detection of transplant rejection.

Chronic active antibody-mediated rejection (AMR) is the leading cause of death-censored kidney allograft loss, with no proven treatments. While intravenous immunoglobulin (IVIG) has been used in certain cases, its efficacy is unknown.

In this open-label multicenter randomized controlled trial (VIPAR), participants with biopsy-proven chronic active AMR, were assigned to six doses (1g/kg/month) of IVIG or no-IVIG. The primary endpoint was the difference in slopes of the chronic allograft damage index (CADI) scores between groups, across four allograft biopsies (baseline, three, six and 12-months). Secondary outcomes, assessed at baseline, three, six and 12-months, included change in estimated glomerular filtration rate (eGFR), change in donor specific anti-HLA antibodies (DSA), allograft and patient survival, and change in intra-graft mRNA expression.

Fifteen participants were randomized to each arm. Their median age was 54.3 years, 22 were male and mean eGFR was 43.3 ml/min/1.73m2. Participants in the no-IVIg group experienced a significant increase in mean CADI (+0.28/month, 95% confidence interval 0.14 to 0.41), while the IVIG group did not (-0.004/month, - 0.13 to 0.12). Over two years, eGFR significantly declined more rapidly in the no-IVIG group (-1.1 ml/min/month, -1.5 to -0.7 ml/min/month) than the IVIG group (-0.4 ml/min/month, - 0.8 to 0.03 ml/min/month). Differences in patient and allograft survival were not evident by 12 months. Intra-graft expression of 59 genes (mostly B-cell related) reduced with IVIG relative to no-IVIG.

IVIG therapy was associated with stabilization in allograft histology and eGFR in kidney transplant recipients with chronic active AMR.

Currently, approximately 90,000 patients are on the kidney transplant waitlist in the United States, including 10,000 individuals awaiting re-transplantation due to prior graft failure. Allograft rejection remains a leading cause of kidney transplant failure. While the current gold standard for diagnosing rejection is tissue biopsy, it is invasive and impractical for routine or longitudinal graft surveillance. This review summarizes the current landscape of non-invasive biomarkers for detecting and predicting kidney transplant rejection, with a focus on both historical context and recent advancements. In particular, we highlight the roles of donor-derived cell-free DNA (dd-cfDNA) and gene expression profiling (GEP) in identifying acute rejection. We also discuss emerging biomarkers such as torque teno virus (TTV), which has shown potential as an indirect indicator of immunosuppression levels and rejection risk. Importantly, this review excludes biomarker studies that rely on tissue biopsy, emphasizing non-invasive approaches to rejection monitoring.

Chronic-active antibody mediated rejection (caAMR) is the leading causes of long-term kidney graft failure. Tocilizumab (TCZ), an anti-IL-6 receptor antibody, has been suggested as a treatment, but data are conflicting. We retrospectively studied consecutive adult kidney transplant recipients with caAMR or microvascular inflammation (MVI) without Donor-Specific Antibodies (DSA) and without C4d deposition (MVI + DSA-C4d-), who received TCZ as first-line therapy in two European centers. Estimated glomerular filtration rate (eGFR) and DSA were assessed one-year before and after TCZ initiation. The study included 64 patients who received TCZ between July 2018 and September 2023. The eGFR trajectory significantly decreased after TCZ treatment (-1.2 ± 0.2 vs. 0.03 ± 0.2 mL/min/1.73 m2/month pre- vs. post-TCZ, respectively; p = 0.001). The percentage of patients with DSA decreased from 63.9% to 38.9% (p < 0.001), and the average MFI decreased from 9,537 to 7,250 (p = 0.001). In multivariate analysis, younger age (OR = 0.95, p = 0.02), MVI + DSA-C4d- phenotype (OR = 5.2, p = 0.01), and lower chronic glomerulopathy score (OR = 4.5, p = 0.02) were associated with TCZ response (trajectory ≥0 after TCZ). Patient survival was 98.4%, and graft survival was 93.7% at one-year. First-line TCZ therapy for caAMR or MVI + DSA-C4d- is associated with an improvement of eGFR trajectories, reduced DSA numbers and MFI and histological inflammation in glomeruli. These data suggest a potential benefit of TCZ in these settings.

Antibody-mediated rejection (AMR) remains a major challenge in clinical transplantation. Current therapies have yielded inconsistent outcomes, highlighting the need for innovative approaches. CD38, a multifunctional glycoprotein, is highly expressed on plasma cells and natural killer (NK) cells, potentially offering a dual mechanism of action that could intervene in the pathophysiologic course of AMR: depleting alloantibody-producing plasma cells and NK cells. This review focuses on recent results from CD38-targeted therapies, with felzartamab emerging as a promising option. Previous case reports and series suggested that off-label daratumumab treatment could effectively reverse AMR. Felzartamab has now demonstrated safety and efficacy in a phase 2 trial for late AMR. Reductions in microvascular inflammation, downregulation of rejection-associated transcripts, and decreases in donor-derived cell-free DNA paralleled a substantial decrease in NK cell counts. However, felzartamab did not significantly affect donor-specific antibodies, which may reflect its distinct mechanism of action, primarily involving antibody-dependent cellular cytotoxicity and phagocytosis. The effects on rejection activity may have a rapid onset, but are transient. The potential benefits of prolonged therapy are currently being investigated in a recently launched phase III trial. Future studies may expand the applications of CD38 targeting to early AMR or broader indications, such as DSA-negative microvascular inflammation.

This meta-analysis aimed to quantify sensitization rates following allograft usage and determine whether allografts have an increased risk of long-term sensitization compared to alternative therapies in burn patients.

Systematic review, meta-analysis and meta-regression of post-operative sensitization in burn patients were performed following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidance (Prospero registration: CRD42024497137). Database searches were conducted on MEDLINE, Embase, CENTRAL using ProQuest Dialog. We included all studies reporting post-operative sensitization in burn patients that were not case series or singular case reports. Meta-analysis was used to compare the risk of sensitization for allograft versus alternative therapies.

Six studies (Allograft Patients: 71; Non-Allograft Patients: 95) were included (n = 166). Overall, 73 % (CI: 39 %-92 %) of burn patients were sensitized following allograft. Patients receiving allograft were at a significantly increased risk of sensitization (OR 13.14 [95 % CI: 1.32-131.00]). However, on sub-group analysis, when directly comparing patients who received allograft and transfusion versus those who received transfusion alone, there was not a significantly increased risk of sensitization (OR 7.68 [95 % CI:.61-95.86]).

Allograft is associated with a significantly increased risk of sensitization in burn patients. However, it is not clear whether burn patients already receiving transfusion will have an increased risk of sensitization from adding allograft. Further studies are required to demonstrate the multifactorial causes of sensitization within the burned population to explain the significance of the contribution from allograft and/or transfusion reported within the literature. Clinicians must carefully weigh the immediate benefits of allografts against the potential long-term challenges of sensitization, especially where alternative wound therapies are possible.

Kidney transplantation remains the preferred treatment for patients with end-stage kidney failure. Complement-dependent cytotoxicity (CDC) crossmatch (CDC-XM) and human leukocyte antigen (HLA) typing are two important methods of donor-recipient matching prior to kidney transplantation. The purpose of the present study was to explore the effects of CDC-XM levels and HLA matching on early post-operative clinical outcomes in kidney transplant recipients. A total of 112 consecutive recipients who underwent allogeneic kidney transplantation were selected and their data collected, including pre-operative general information, indicators associated with renal function, red blood cell and white blood cell counts, the blood glucose level at each follow-up time point and both the incidence of adverse events following transplantation and their risk factors. During the follow-up period, statistical methods were used to compare and systematically analyze the differences in clinical indicators and adverse events between each groups. In each different groups that were assigned for the CDC-XM levels and HLA matching, the differences in the clinical indicators between the groups during the follow-up period were mainly centered on the first week post-transplantation, with the greatest differences being identified for the renal function-associated indicators, whereas the observed recovery was essentially comparable between 1-6 months. According to the multivariate analysis, recipients of age ≥40 years and with a BMI ≥25 tended to have an increased risk of delayed graft function (DGF), whereas the risk was reduced when the organ had been donated by a living donor and also when the number of HLA mismatches was 0-2. In conclusion, the present study showed that CDC-negativity and improved HLA matching help to promote the recovery of renal function in kidney transplant recipients during the early post-operative period. Patients who met the conditions of CDC-negativity and fewer HLA mismatches had faster and improved early postoperative recovery of renal function and a lower incidence of DGF. Furthermore, in a multifactorial analysis of DGF, recipient age, recipient BMI, donor type and HLA mismatch were found to be important risk factors for DGF.

Recent evidence highlights the pivotal role of natural killer (NK) cells in allograft rejection.

We explored associations of missing self and gene polymorphisms determining the phenotype and/or functionality of NK cells with microvascular inflammation (MVI) in a single-center cohort of 507 consecutive kidney transplant recipients. Patients were genotyped for killer cell Ig-like receptors and polymorphisms in 4 selected genes ( FCGR3AV/F158 [rs396991], KLRC2wt/del , KLRK1HNK/LNK [rs1049174], and rs9916629-C/T).

MVI was detected in 69 patients (13.6%). In a proportional odds model, the KLRC2del/del variant reduced MVI risk (odds ratio [OR] 0.26; 95% confidence interval [CI], 0.05-0.93; P  = 0.037) independent of donor-specific antibodies, HLA class II eplet mismatch, and number of biopsies. Conversely, missing self (OR 1.40; 95% CI, 1.08-1.80; P  = 0.011) and the rs9916629 T/T gene variant increased the risk (OR 1.70; 95% CI, 1.08-2.68; P  = 0.021). Graft loss tended to be more frequent among patients with missing self ≥2 (hazard ratio 1.97; 95% CI, 0.89-4.37; P  = 0.097), without influence on estimated glomerular filtration trajectories. FCGR3A variants were associated with MVI only in patients with preformed and/or de novo donor-specific antibodies (OR 4.14; 95% CI, 0.99-17.47; P  = 0.052).

Missing self and NK-cell genetics may contribute to MVI, underscoring the important role of NK cells in transplant rejection.

Interleukin-21 (IL-21) is a cytokine that plays a crucial role in regulating immune responses, affecting various immune cell types, including T cells, B cells, natural killer (NK) cells, and dendritic cells. IL-21 is primarily produced by CD4+ T cells, particularly follicular helper T (Tfh) cells and Th17 cells, and has been shown to be extensively involved in regulating both innate and adaptive immunity. IL-21 is particularly significant in the differentiation, proliferation, and effector functions of T cells and B cells. In the context of organ transplantation, IL-21 contributes to the promotion of acute transplant rejection and the development of chronic rejection, which is primarily antibody-mediated. This review summarizes relevant studies on IL-21 and discusses its multifaceted roles in transplant immune rejection, providing insights into therapeutic strategies for either inhibiting graft rejection or promoting tolerance. It also explores the feasibility of blocking the IL-21 signaling pathway within current immunosuppressive regimens, aiming to provide further clinical references.

Antibody-mediated rejection (AMR) is a leading cause of kidney graft failure. Complement activation is involved in the AMR process. Our aim is to provide the current understanding of the pathophysiology related to complement-mediated injury in AMR, to present the current evidence regarding complement blockade in AMR management, and to point out emerging therapies and future directions in this area. The complement system plays an important role in the onset and progression of AMR. There is a balance between complement-dependent and -independent mechanisms in the development of rejection lesions. Classic and leptin pathways are involved in this process. C4d positivity is no longer a mandatory feature for AMR diagnosis but remains an independent predictor of negative outcomes. The current evidence regarding AMR treatment is limited. Terminal and proximal complement blockade has gained recognition in clinical practice. Eculizumab and C1 inhibitors are effective in the treatment of AMR as adjuvant therapies to the standard of care. The availability of novel complement inhibitors will lead to more effective and tailored treatment strategies.

HLA-DQ antibodies are the most prevalent de novo donor-specific antibodies (dnDSAs) after kidney transplantation (KT). The immunogenicity and impact of each HLA-DQ mismatch on graft outcomes can vary considerably.

This retrospective cohort study investigated the prevalence and risk factors for dnDSA development in patients who underwent KT at Siriraj Hospital between 2006 and 2020 and had HLA-DQB1 mismatches. Our center employed a protocol for post-KT dnDSA surveillance. The impact of dnDSAs on late rejection and graft survival was evaluated.

In our cohort of 491 KT recipients, 59 (12.02%) developed dnDSAs to HLA-DQB1 at a median time of 4.2 years after KT. The risk of dnDSA occurrence was significantly higher among recipients with HLA-DQ7 mismatch (HR: 2.8; 95% CI: 1.21-6.52; P = 0.017) and HLA-DQ9 mismatch (HR: 2.63; 95% CI: 1.11-6.27; P = 0.028). Recipients who developed dnDSAs were younger (P = 0.009), had higher rates of medication nonadherence (P = 0.031), had pre-KT panel reactive antibody levels above 20% (P = 0.044), and received non-tacrolimus immunosuppression (P < 0.001) compared to those without. Recipients who developed dnDSAs to HLA-DQ exhibited a significantly higher incidence of late graft rejection (HR: 7.76; 95% CI: 5-12.03; P < 0.0001) and inferior death-censored graft survival than those without dnDSAs (log rank P < 0.001).

The patients with HLA-DQ7 and HLA-DQ9 mismatches exhibit the highest risk of developing dnDSAs. Individualized immunosuppression adjustment and kidney allocation based on specific HLA-DQ mismatch may enhance long-term graft survival.

Background/Objectives: The tacrolimus (Tac) concentration-to-dose ratio (C/D ratio) has been described as a predictive marker for several outcome parameters after renal transplantation (RTx). Different C/D ratio values are used to define fast (low C/D ratio) and slow Tac metabolizers (high C/D ratio). In this study, the R package was used to determine the optimal C/D ratio cut-off value to define the Tac metabolism type with a high predictive value for the development of renal function. Methods: The data of 389 RTx patients who received an initial immunosuppression with immediate-release tacrolimus (IR-Tac), mycophenolate, prednisolone, and an induction with basiliximab were analyzed. The Tac C/D ratio (ng/mL × 1/mg) of all patients was calculated 3 months after RTx and the maximally selected Wilcoxon statistic was applied to determine the optimal C/D ratio cut-off value for renal function development over a 5-year follow-up. Results: A C/D ratio of 0.94 provided the optimal differentiation between fast and slow Tac metabolism in relation to renal function development at 1, 2, 3, and 4 years of follow-up, and at 0.95 five years after RTx. Conclusions: As fast Tac metabolism is associated with the development of an impaired renal function, it is essential to identify patients at risk early after RTx. In order to keep the application simple for clinical routine, we suggest calculating the C/D ratio 3 months after RTx and using 1.0 (≤1.0 = fast metabolizer) as the cut-off, which is very close to the optimal value.

Successful allograft-specific tolerance induction would eliminate the need for daily immunosuppression and improve posttransplant quality of life. Adoptive cell therapy with regulatory T cells expressing donor-specific chimeric antigen receptors (CAR Tregs) is a promising strategy but, as monotherapy, cannot prolong survival with allografts with multiple MHC mismatches. Using an HLA-A2-transgenic haplo-mismatched heart transplantation model in immunocompetent C57BL/6 recipients, we showed that HLA-A2-specific CAR (A2.CAR) Tregs were able to synergize with a low dose of anti-CD154 to enhance graft survival. Using haplo-mismatched grafts expressing the 2W-OVA transgene and tetramer-based tracking of 2W- and OVA-specific T cells, we showed that in mice with accepted grafts, A2.CAR Tregs inhibited donor-specific T cell, B cell, and antibody responses and promoted a substantial increase in endogenous FOXP3+ Tregs with indirect donor specificity. By contrast, in mice where A2.CAR Tregs failed to prolong graft survival, FOXP3- A2.CAR T cells preferentially accumulated in rejecting allografts, and endogenous donor-specific responses were not controlled. This study therefore provides evidence for synergy between A2.CAR Tregs and CD154 blockade to promote infectious tolerance in immunocompetent recipients of haplo-mismatched heart grafts and defines features of A2.CAR Tregs when they fail to reshape host immunity toward allograft tolerance.

ObjectivesThe aim of the present study was to compare the differences in clinical outcomes within 6 months postoperatively between a complement-dependent cytotoxicity <10% group of low-risk kidney transplant patients and a complement-dependent cytotoxicity ≥10% group of relatively high-risk patients.MethodsThe clinical data of 330 patients who underwent kidney transplantation were retrospectively analyzed. The patients were divided into three groups according to the results of complement-dependent cytotoxicity crossmatch: (a) group 1 (complement-dependent cytotoxicity ≥10%); (b) group 2a (5% ≤ complement-dependent cytotoxicity < 10%); and (c) group 2b (complement-dependent cytotoxicity <5%). The clinical outcomes were compared between the three groups.ResultsSignificant differences were noted in serum creatinine levels and estimated glomerular filtration rate between groups 2a and 2b on days (D) 1, 2, 3, and 7 (P < 0.005). From postoperative D1 to month (M) 6, a significant difference (P < 0.05) was noted in urea levels between the three groups. On D3, blood glucose levels were significantly lower in group 2b than in group 2a (P < 0.001); at M6, group 2b exhibited lower blood glucose levels than group 1 (P = 0.043). On D2, group 2b had a lower neutrophil percentage than group 1 (P < 0.05), which was significantly different from those of groups 1 and 2a on D3 (P < 0.05). The percentage and absolute number of lymphocytes in group 2b were significantly higher than those in group 1 (P < 0.01) on D1 and D2. The percentage and absolute number of lymphocytes were significantly higher in group 2b than in groups 1 and 2a on D3 and D7 (P < 0.05).ConclusionsComplement-dependent cytotoxicity <10%, particularly complement-dependent cytotoxicity <5%, was associated with superior attributes compared with complement-dependent cytotoxicity ≥10% in terms of most aspects of postoperative recovery and low incidence of adverse events. However, delayed graft function rate was highest in the complement-dependent cytotoxicity of 5%-10% group. The source of donor kidneys was the most important factor influencing delayed graft function, and a larger cohort with a longer follow-up period may be needed to verify the tendency.

In kidney transplantation, ongoing alloimmune processes-commonly triggered by HLA incompatibilities-can trigger chronic transplant rejection, affecting the microcirculation and the tubulointerstitium. Continuous inflammation may lead to progressive, irreversible graft injury, culminating in graft dysfunction and accelerated transplant failure. Numerous experimental and translational studies have delineated a complex interplay of different immune mechanisms driving rejection, with antibody-mediated rejection (AMR) being an extensively studied rejection variant. In microvascular inflammation, a hallmark lesion of AMR, natural killer (NK) cells have emerged as pivotal effector cells. Their essential role is supported by immunohistologic evidence, bulk and spatial transcriptomics, and functional genetics. Despite significant research efforts, a substantial unmet need for approved rejection therapies persists, with many trials yielding negative outcomes. However, several promising therapies are currently under investigation, including felzartamab, a monoclonal antibody targeting the surface molecule CD38, which is highly expressed in NK cells and antibody-producing plasma cells. In an exploratory phase 2 trial in late AMR, this compound has demonstrated potential in resolving molecular and morphologic rejection activity and injury, predominantly by targeting NK cell effector function. These findings inspire hope for effective treatments and emphasize the necessity of further pivotal trials focusing on chronic transplant rejection.

Antibody-mediated rejection (ABMR) is a major cause of graft loss in kidney transplantation, often associated with de novo donor-specific antibodies (dnDSA). The detection of clinically relevant dnDSA relies on evaluating reactivity in single antigen bead (SAB) assays. Immunogenetic mismatches between donor and recipient, particularly involving human leukocyte antigens (HLA), underpin dnDSA development. Understanding this relationship could improve pre-transplant risk assessment and organ allocation.

We analyzed 1296 kidney transplant patients to study dnDSA development, its relation to age, gender, and the role of HLA-derived peptide mismatches using the Predicted Indirectly Recognizable HLA Epitopes II (PIRCHE II) score. We categorized dnDSA based on bead reactivity patterns and HLA typing into true, possible, and false dnDSA.

During follow-up, 25% of recipients developed dnDSA, 9.3% true, 7.7% possible, and 7.9% false. True dnDSA primarily targeted HLA-DQ (38%), while HLA-C and HLA-DP were uncommon (5% and 3%). Higher PIRCHE II scores were significantly associated with true and possible dnDSA against HLA Class II compared to false dnDSA, supporting our dnDSA classification. For true and possible dnDSA, the single locus PIRCHE II score strongly correlated with locus-specific dnDSA, while the total PIRCHE II score did not appear to influence locus-specific dnDSA development. Younger recipients exhibited a higher risk of dnDSA development, while gender had no impact.

Locus-specific PIRCHE II scores are useful in predicting dnDSA risk post-transplantation, particularly in younger recipients. Promoting transplants with low PIRCHE II scores against key HLA loci like HLA-DQ in younger recipients could improve outcomes.

Extracellular purines not only play a critical role in maintaining a balanced inflammatory response but may also trigger disproportionate inflammation in various kidney pathologies. Extracellular ATP is the most well-characterized inflammatory purine, which serves as a potent extracellular danger-associated molecular pattern ( i.e ., danger-associated molecular pattern). It signals through the P2 purinoreceptors during both acute and chronic kidney damage. The purinoreceptor P2X7 (P2X7R) has been extensively studied in kidney disease because of its potent ability to enhance inflammation by activating the nucleotide-binding oligomerization domain, leucine rich repeat family pyrin domain containing 3 inflammasome in both immune and parenchymal tubular cells and potential role in immunometabolic reprogramming. We will explore how, following a primary insult to the kidney, disturbance of purinergic balance characterized by extracellular ATP-mediated P2X7R activation exacerbates AKI. Second, we will describe how persistent purinergic disbalance promotes a P2X7R-mediated protracted inflammatory reaction leading to the progression of CKD of different etiologies. Finally, we will also highlight the relevant and emerging role of P2X7R signaling in both antigen-presenting cells and adaptive immune cells to modulate cellular and humoral immune responses in kidney transplantation and hypertension. This review underscores that ATP-P2X7R axis is a key driver of pathologic purinergic signaling, representing a largely unexplored but highly promising clinical target against a wide spectrum of kidney diseases.

Chronic kidney disease (CKD) is globally prevalent, a leading cause of mortality, and is associated with poor patient outcomes and high healthcare costs. Gaps in guideline-concordant care are common across the continuum of CKD. These gaps lead to CKD progression, hospitalizations, and mortality, and are potentiated by existing racial and socioeconomic disparities. A thoughtfully designed population health management approach, that leverages electronic health record, can modernize CKD care delivery and improve outcomes. Such an approach can potentially provide timely, equitable, resource- and cost-efficient care across health systems in a way that is scalable and data driven. Herein, we share our experiences with the implementation of nephrology population health initiatives at the University of Pittsburgh Medical Center across the CKD spectrum, which include ongoing and planned programs in the primary care, kidney-palliative care, kidney transplantation, and transitions of care settings. Further, we discuss the challenges of population health management and future directions that can move healthcare toward personalized medicine.

HLA matching is critical for successful kidney transplantation. This study aimed to investigate the impact of eplet mismatches and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II) scores on the development of de novo donor-specific antibodies (dnDSA) and graft survival in a Tunisian cohort, characterized by a high prevalence of living donors and significant genetic diversity in HLA profiles.

This retrospective study included 112 adult kidney transplant recipients who underwent transplantation between 2012 and 2018. Donor and recipient HLA typing was performed using One Lambda Labtype PCR-SSO and PCR-SSP kits, with high-resolution typing inferred using validated tools and reference datasets. Luminex DSA screening (One Lambda) was conducted at transplantation, during follow-up for graft dysfunction or proteinuria, and at the study's conclusion. Eplet mismatches and PIRCHE-II scores were calculated using EpVix and PIRCHE-II software.

Nineteen patients (17 %) developed dnDSA, predominantly targeting HLA-DQ, with a median detection timeframe of 50 months (range: 11-106 months) post-transplantation. Male donor sex was negatively associated with dnDSA development, while prolonged cold ischemia time was a significant risk factor. Molecular HLA-DQ mismatches and high PIRCHE-II scores were significantly associated with dnDSA. Factors independently associated with reduced death-censored graft survival included history of transfusion after transplantation, allelic DRB1 mismatch, dnDSA development, and elevated PIRCHE-II score.

Our findings highlight the critical role of HLA-DQ compatibility in kidney transplantation and suggest that molecular HLA-DQ matching should be considered in kidney allocation strategies to minimise alloimmune responses and improve long-term graft outcomes.

Renal transplant recipients with donor-specific anti-HLA antibodies are at an increased risk of antibody-mediated rejection (ABMR). Early protocolized renal biopsies may serve as a strategy to improve diagnosis in this patient population.

We evaluated 155 highly sensitized renal transplant recipients with cPRA class I + II >90% pre-transplant from 2015 to 2022. Patients with protocol biopsies within the first 2 weeks post-transplant were included.

A total of 122 patients were included in the study. Of these, 13 (10.6%) were diagnosed with very early antibody-mediated rejection (veABMR) within the first 2 weeks post-transplant. This corresponds to 52% (13/25 patients) of all ABMR cases reported during the follow-up of this population. The graft survival rates at 1 and 3 years were significantly lower in patients with veABMR (P < .001) compared with patients without rejection in the early protocol biopsy. In terms of severity, the veABMR cohort exhibited a hazard ratio (HR) of 10.33 (95% confidence interval 3.23-33.06, P < .001) for graft failure. The presence of donor-specific antibodies class II on the day of transplantation and a higher percentage of eplet mismatch (EpMM), particularly EpMM DQA1, correlated with the development of veABMR.

Early protocol biopsies play a pivotal role in the early detection of veABMR in high-risk immunological patients. Patients with veABMR face significant risks of graft loss, despite early treatment of rejection.

Background: Kidney transplantation (KTx) is a safe procedure that improves the life expectancy and quality of life of patients requiring it. However, despite the known benefits for patients who receive a kidney transplant, non-adherence to immunosuppressive medication is an unsolved problem, reflected mainly by graft rejection. Objective: The aim of this study is to systematically review the existing literature on adherence factors to medication after renal transplantation. Methods: A systematic literature review of studies published since 2010 was conducted in three databases. Records for the search were limited to publications from 2010 to 2024, available in full-text. The search was carried out in July 2024. In total, 2632 abstracts were downloaded from the different databases. Inclusion criteria were papers of any type (quantitative or qualitative) whose objective was the identification of predictors of adherence for patients who were prescribed immunosuppressive medication after kidney transplantation. Results: The predictors of adherence to treatment found in the systematic review were grouped into the following categories of the World Health Organization classification: socio-economic factors, factors related to the treatment/therapy, patient-related factors, disease-related factors, and health care system factors. Most of the studies were excluded, and in the end, 30 were included in the final analysis. According to these studies, a set of strong predictors was identified, but discrepancies among the variables of gender in young patients, pre-emptive transplantation, and the time of the transplantation were detected. Conclusions: In this study, we identified specific predictors and directions for the association of those predictors with adherence to immunosuppressive medication for patients after KTx. Further research should consider conducting reviews for different patient sub-groups on medication adherence and the development and validation of a screening instrument for adherence/non-adherence factors that clinicians could use as a detection tool for subjects at risk of low adherence.

In the last two decades, many studies based on omics technologies have contributed to defining the clinical, immunological, and histological fingerprints of chronic antibody-mediated rejection (CAMR), the leading cause of long-term kidney allograft failure. However, the full biological machinery underlying CAMR has only been partially defined, likely due to the fact thatsingle-omics technologies capture only specific aspects of the biological system and fail to provide a comprehensive understanding of this clinical complication.

This study integrated mass spectrometry-based proteomic profiling of serum samples from 19 patients with clinical and histological evidence of CAMR and 26 kidney transplant recipients with normal graft function and histology (CTR) with transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from an independent cohort of 10 CAMR and 8 CTR patients. Data analysis was conducted using unsupervised hierarchical clustering (multidimensional scaling with k-means) and Spearman's correlation test. Partial least squares discriminant analysis (PLS-DA) with the importance in projection (VIP) score identified key proteins differentiating CAMR from CTR. ELISA was used to validate the omics results.

Proteomic analysis identified 18 proteins that significantly differentiated CAMR from CTR (p < 0.01): five were more abundant (CHI3L1, LYZ, PRSS2, CPQ, IGLV3-32), while 13 were less abundant (SERPINA5, SERPING1, KNG1, CAMP, VNN1, BTD, WDR1, PON3, AHNAK2, MELTF, CA1, CD44, CUL1). Transcriptomic profiling revealed 6 downregulated and 33 upregulated genes in CAMR versus CTR (p < 0.01). Notably, only 2 biological elements were significantly deregulated in both omics analyses: chitinase-3-like protein 1 (CHI3L1) and plasma protease inhibitor C1 (SERPING1). CHI3L1, previously associated with the severity of tissue damage in kidney diseases, was up-regulated in CAMR in both transcriptomics and proteomics, while SERPING1, a serine esterase inhibitor that blocks the classical and lectin pathway of complement, was up-regulated in CAMR in transcriptomics but down-regulated in proteomics. ELISA validated the omics results, and the ROC curve showed that CHI3L1 has good discrimination power between CAMR and CTR (AUC of ROC curve of 0.81).

Our multi-omics data, although performed in a relatively small cohort of patients, revealed new systemic biological elements involved in the pathogenesis of CAMR and identified CHI3L1 as a new potential biomarker and/or therapeutic target for this important clinical complication. Future validation of these findings in larger patient cohorts should be conducted to better evaluate their clinical utility.

Objectives: The aim of this study was to assess the HLA alloreactivity of cold-stored saphenous vein allografts (CSVAs) by identifying the production of HLA donor-specific antibodies (DSAs) in the recipient. The secondary objective was to evaluate CSVA rejection-related complications, such as CSVA thrombosis and/or aneurysmal degeneration in the recipient. Methods: This was a single-center, prospective, experimental before-and-after study which included participants undergoing CSVA placement, either to create a vascular access (VA) for hemodialysis or to create a lower limb arterial bypass. On Day 1, before CSVA placement, total blood samples were taken for HLA typing by sequence-specific primers (SSPs) and anti-HLA antibody detection using a Luminex assay. One month after CSVA placement, a second blood sample was taken to assess the appearance of donor-specific antibodies or an increase in the level of anti-HLA antibodies. Patency of the CSVA and potential aneurysmal degeneration were evaluated at 3 and 6 months with a Doppler ultrasound checkup. Results: From September 2022 to November 2023, 45 patients were included (30 men, 67%; mean age: 71 ± 12 years). One month after CSVA placement, no appearance of de novo anti-HLA antibody was detected in anti-HLA antibody-negative patients at inclusion (n = 28). Among the patients who already had anti-HLA antibodies at inclusion (n = 17), no increase in anti-HLA antibody levels or appearance of de novo anti-HLA antibodies was detected. Conclusions: This prospective study evaluating the immunogenicity of CSVAs through the appearance of anti-HLA antibodies one month after placement demonstrates that they do not seem to induce any HLA alloreactivity. Therefore, they may be used without the risk of HLA immunization in patients awaiting organ transplantation.

Surveillance donor-specific antibody (DSA) and pathologic antibody-mediated rejection (pAMR) testing is recommended in the first year after heart transplantation (HTx) in adult patients. Whether pAMR testing adds prognostic information to contemporary DSA testing has not been fully studied.

This was a single-center study of consecutive endomyocardial biopsies (EMB) performed between November 2010 and February 2023 in adult HTx patients. The primary objective was to evaluate whether pAMR testing contributes additional information to DSA testing to better predict overall survival. Secondary end-points included cardiac survival and allograft dysfunction.

A total of 6,033 EMBs from 544 HTx patients were reviewed for the study. The pAMR+/DSA+ patients had significantly lower overall (pc = 0.013) and cardiac survival (pc = 0.002), while the pAMR+/DSA- and pAMR-/DSA+ patients showed no difference in either outcome compared to the pAMR-/DSA- group. We found significantly lower overall survival in pAMR+/DSA+ patients with allograft dysfunction (pc < 0.001) but not in pAMR+/DSA+ patients without allograft dysfunction (pc = 0.569), when compared to the pAMR-/DSA- without allograft dysfunction group. The pAMR+/DSA+ patients with cardiac allograft dysfunction accounted for 18% of deaths or cardiac retransplants while only representing 4% of the HTx cohort. Moderate or severe primary graft dysfunction (PGD) also was a novel risk factor for the development of de novo DSAs (dnDSA) by 4 weeks post-HTx (p = 0.025).

Surveillance DSA testing may effectively identify high-risk pAMR+ patients. Earlier DSA testing at 10 to 14 days post-HTx should also be considered in moderate or severe PGD patients.

Microvascular inflammation (MVI) is an important pathological feature of antibody-mediated rejection (AMR). How posttransplant time affects its clinicopathological expression is little understood.

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.

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.

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.

Alloprimed antibody-suppressor CXCR5+CD8+ T cells (CD8+ TAb-supp cells) downregulate alloantibody production, mediate cytotoxicity of IgG+ B cells, and prolong allograft survival. The purpose of this investigation was to determine which immune-cell subsets are susceptible to CD8+ TAb-supp cell-mediated cytotoxicity or noncytotoxic suppression.

Alloprimed immune-cell subsets were evaluated for susceptibility to CD8+ TAb-supp cell-mediated in vitro cytotoxicity and/or suppression of intracellular cytokine expression. In vivo CD8-mediated cytotoxicity to wild-type germinal center (GC) B cells or wild-type CD4+ T follicular helper cells (TFH cells) was assessed in RAG1 knockout mice. The impact of in vivo adoptive transfer of CD8+ TAb-supp cells into hepatocyte or kidney transplant recipients on the quantity of lymphoid immune-cell subsets was assessed.

CD8+ TAb-supp cells mediated allospecific cytotoxicity to alloprimed GC B cells but not alloprimed extrafollicular plasmablasts, marginal zone B cells, follicular B cells, or plasma cells. CD8+ TAb-supp cells did not mediate cytotoxicity to alloprimed dendritic cells, macrophages, CD4+ TFH cells, CD4+ T follicular regulatory cells, or CD4+ regulatory T cell. CD8+ TAb-supp cells did not suppress CD4+ TFH cell, T follicular regulatory cell, or regulatory T-cell cytokine expression. Adoptive transfer of CD8+ TAb-supp cells into hepatocyte or kidney transplant recipients reduced alloantibody production and the quantity of GC B cells, TFH cells, and plasma cells (but not other B-cell, T-cell, or antigen-presenting cell subsets). The reduction of TFH-cell quantity was dependent on CD8+ TAb-supp cell-mediated major histocompatibility complex-I-dependent cytotoxic killing of GC B cells.

The primary targets of CD8+ TAb-supp cells are GC B cells with downstream reduction of TFH and plasma cells.

The generation of donor-specific antibodies (DSA) requires that alloreactive B cells receive help from follicular helper T (TFH) cells. Recent works have suggested that γδ T cells could contribute to T cell-dependent humoral responses, leading us to investigate their role in DSA generation. Analysis of a cohort of 331 kidney transplant recipients found no relation between the number of circulating γδ T cells and the risk to develop DSA. Coculture models demonstrated that activated γδ T cells were unable to promote the differentiation of B cells into plasma cells, ruling out that they can be "surrogate" TFH. In line with this, γδ T cells preferentially localized outside the B cell follicles, in the T cell area of lymph nodes, suggesting that they could instead act as "antigen-presenting cell" (APC) to prime αβ TFH. This hypothesis was proven wrong since γδ T cells failed to acquire APC functions in vitro. These findings were validated in vivo by the demonstration that following transplantation with an allogeneic Balb/c (H2d) heart, wild-type and TCRδKO C57BL/6 (H2b) mice developed similar DSA responses, whereas TCRαKO recipients did not develop DSA. We concluded that the generation of DSA is unfazed by the absence of γδ T cells.

Patients with end-stage kidney disease often prefer home-based dialysis due to higher self-efficacy, which relates to improved medical treatment adherence. Kidney transplantation (KT) success depends on adhering to immunosuppressive medication post-transplant.

To investigate whether adherence post-kidney transplantation (KT) and patients' attitudes toward immunosuppression were influenced by their prior dialysis type modality. Additionally, the study examined if adherence and patient's attitudes towards immunosuppression are associated with kidney graft survival.

This cross-sectional single-center study included 201 KT patients. Adherence was assessed using BAASIS and the coefficient of variation of calcineurin inhibitors (COV-CNI). Patient attitudes towards medication were evaluated using the Q-method. Pill burden, comorbidity score and HRQoL and medication complexity, were scored. Cox regression was applied to determine KT survival outcomes over a 14-year follow-up period (until Dec 2021).

Prior dialysis modality was not associated with adherence to immunosuppression post-KT evaluated by BAASIS on average 4.7 years post-KT. Previous in-center hemodialysis patients had a higher CNI-COV (p = 0.011). The Q-sort analysis identified fully adherent patients linked to profile 1 (organized, resilient) whereas profile 2 patients were more careless. Patients linked to profile 3 (challenging, nervous) had higher education, a higher pill burden, and experienced more immunosuppression side effects. Death-censored graft loss increased by 7.6% with each additional pill, quadrupled if one dose of immunosuppression was missed, and increased by 2.9% for each point of COV-CNI rise.

Adherence to immunosuppression post-KT using BAASIS was not associated with prior dialysis type, despite in-center hemodialysis patients showing the highest COV-CNI. Taking COV-CNI into account, managing missed doses of immunosuppressants, and exploring patient attitudes could potentially enhance adherence and consequently improve KT survival.

Donor-derived cell-free DNA (dd-cfDNA) is a promising non-invasive biomarker for detecting graft injury in solid organ transplant recipients. Elevated dd-cfDNA levels are strongly associated with rejection and graft injury, especially antibody-mediated rejection (ABMR). While de novo donor-specific antibodies (dnDSA) are crucial in ABMR, the relationship between dd-cfDNA levels and dnDSA features, such as DSA category, MFI and HLA target loci, remains unclear.

We analyzed dd-cfDNA levels in 75 kidney transplant recipients who developed dnDSA post-transplant. dnDSA were categorized as "true", "possible", or "false" based on bead reactivity patterns and HLA typing. dd-cfDNA was assessed alongside dnDSA detection and sequential follow-up samples in a subgroup.

"True" dnDSA showed significantly higher dd-cfDNA levels compared to "possible" and "false" groups. None of the dd-cfDNA values in the "false" group exceeded 0.6%, and only a small fraction of the "possible" group had values slightly above 0.6%. dd-cfDNA levels were not significantly affected by dnDSA target loci or number. A strong correlation between cumulative dnDSA MFI and dd-cfDNA levels was observed, especially in patients with "true" HLA-DQ-directed dnDSA. Sequential dd-cfDNA analysis showed dynamic changes in 25% of patients, all from the "true" dnDSA group, which tended to align with shifts in cumulative MFI over time.

These findings highlight the correlation between cumulative dnDSA MFI and dd-cfDNA levels, particularly in HLA-DQ-directed dnDSA, and suggest graft injury is dynamic in dnDSA-positive patients. Integrated monitoring of dnDSA and dd-cfDNA offers a promising non-invasive approach for assessing graft injury and alloimmunity, potentially enhancing post-transplant care.

Current desensitization and maintenance immunosuppression regimens for kidney transplantation in sensitized individuals show limited ability to control the posttransplant humoral response, resulting in high rates of antibody-mediated rejection (ABMR) and graft failure. Here, we showed that anti-CD154 monoclonal antibody (mAb)-based immunosuppression more effectively controlled allograft rejection and humoral rebound in a highly sensitized nonhuman primate kidney transplantation model compared with tacrolimus-based standard-of-care (SOC) immunosuppression. Desensitization with an anti-CD154 mAb (5C8) and a proteasome inhibitor led to decreased donor-specific antibodies (DSAs) and disruption of lymph node germinal centers with reduction of proliferating, memory, and class-switched B cells as well as T follicular helper cells. After transplant, the nonhuman primates maintained on 5C8-based immunosuppression had significantly better survival compared with those maintained on SOC immunosuppression (135.2 days versus 32.8 days, P = 0.013). The 5C8-treated group demonstrated better suppression of DSAs after transplant, more robust suppression of B cell populations, and better induction of regulatory T cells. Fewer infectious and welfare complications, including viral reactivation and weight loss, were also observed with 5C8-based immunosuppression compared with SOC immunosuppression. Therefore, anti-CD154 mAbs may improve kidney transplant outcomes through better control of posttransplant immune responses. The superior efficacy of anti-CD154 mAb-based immunosuppression over tacrolimus-based SOC seen in this highly sensitized NHP transplant model suggests that anti-CD154 mAbs could potentially be used to desensitize and treat highly sensitized patients receiving kidney transplantation.