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The intracellular tacrolimus concentration in CD3+ T lymphocytes is proposed to be a better representative of the active component of tacrolimus than the whole blood concentration. However, intracellular measurements are complicated. Therefore, the aim of this study was to describe the relationship between intracellular and whole blood tacrolimus concentrations in a population pharmacokinetic model. Twenty-eight de novo kidney transplant recipients, treated with a once-daily oral extended-release tacrolimus formulation, were followed during the first-month post-transplantation. Additional whole blood and intracellular tacrolimus concentrations were measured at day 6 ± 1 (pre-dose, 4 and 8 hours post-dose) and day 14 ± 3 (pre-dose) post-transplantation. Pharmacokinetic analysis was performed using nonlinear mixed effects modeling software (NONMEM). The ratio between intracellular (n = 109) and whole blood (n = 248) concentrations was best described by a two-compartment whole blood model with an additional intracellular compartment without mass transfer from the central compartment. The ratio remained stable over time. Prednisolone dose influenced the absorption rate of tacrolimus, while hemoglobin, CYP3A4*22 allele carrier, and CYP3A5 expresser status were associated with the oral clearance of tacrolimus (P-value < 0.001). Furthermore, the intracellular tacrolimus concentrations were correlated with the intracellular production of interleukin-2 (P-value 0.015). The intracellular tacrolimus concentration can be predicted from a measured whole blood concentration using this model, without the need for repeated intracellular measurements. This knowledge is particularly important when the intracellular concentration is ready to be implemented into clinical practice, to overcome the complexities of cell isolation and analytical methods.
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BACKGROUND: Insight into cellular immune responses to COVID-19 vaccinations is crucial for optimizing booster programs in kidney transplant recipients (KTRs). METHODS: In an immunologic substudy of a multicenter randomized controlled trial (NCT05030974) investigating different repeated vaccination strategies in KTR who showed poor serological responses after 2 or 3 doses of an messenger RNA (mRNA)-based vaccine, we compared SARS-CoV-2-specific interleukin-21 memory T-cell and B-cell responses by enzyme-linked immunosorbent spot (ELISpot) assays and serum IgG antibody levels. Patients were randomized to receive: a single dose of mRNA-1273 (100 µg, nâ =â 25), a double dose of mRNA-1273 (2 × 100 µg, nâ =â 25), or a single dose of adenovirus type 26 encoding the SARS-CoV-2 spike glycoprotein (Ad26.COV2.S) (nâ =â 25). In parallel, we also examined responses in 50 KTR receiving 100 µg mRNA-1273, randomized to continue (nâ =â 25) or discontinue (nâ =â 25) mycophenolate mofetil/mycophenolic acid. As a reference, the data were compared with KTR who received 2 primary mRNA-1273 vaccinations. RESULTS: Repeated vaccination increased the seroconversion rate from 21% to 66% in all patients, which was strongly associated with enhanced levels of SARS-CoV-2-specific interleukin-21 memory T cells (odd ratio, 3.84 [1.89-7.78]; Pâ <â 0.001) and B cells (odd ratio, 35.93 [6.94-186.04]; Pâ <â 0.001). There were no significant differences observed in these responses among various vaccination strategies. In contrast to KTR vaccinated with 2 primary vaccinations, the number of antigen-specific memory B cells demonstrated potential for classifying seroconversion after repeated vaccination (area under the curve, 0.64; 95% confidence interval, 0.37-0.90; Pâ =â 0.26 and area under the curve, 0.95; confidence interval, 0.87-0.97; Pâ <â 0.0001, respectively). CONCLUSIONS: Our study emphasizes the importance of virus-specific memory T- and B-cell responses for comprehensive understanding of COVID-19 vaccine efficacy among KTR.
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Research on solid organ transplantation has taken advantage of the substantial acquisition of medical data and the use of artificial intelligence (AI) and machine learning (ML) to answer diagnostic, prognostic, and therapeutic questions for many years. Nevertheless, despite the question of whether AI models add value to traditional modeling approaches, such as regression models, their "black box" nature is one of the factors that have hindered the translation from research to clinical practice. Several techniques that make such models understandable to humans were developed with the promise of increasing transparency in the support of medical decision-making. These techniques should help AI to close the gap between theory and practice by yielding trust in the model by doctors and patients, allowing model auditing, and facilitating compliance with emergent AI regulations. But is this also happening in the field of kidney transplantation? This review reports the use and explanation of "black box" models to diagnose and predict kidney allograft rejection, delayed graft function, graft failure, and other related outcomes after kidney transplantation. In particular, we emphasize the discussion on the need (or not) to explain ML models for biological discovery and clinical implementation in kidney transplantation. We also discuss promising future research paths for these computational tools.
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Kidney organoids are an innovative tool in transplantation research. The aim of the present study was to investigate whether kidney organoids are susceptible for allo-immune attack and whether they can be used as a model to study allo-immunity in kidney transplantation. Human induced pluripotent stem cell-derived kidney organoids were co-cultured with human peripheral blood mononuclear cells (PBMC), which resulted in invasion of allogeneic T-cells around nephron structures and macrophages in the stromal cell compartment of the organoids. This process was associated with the induction of fibrosis. Subcutaneous implantation of kidney organoids in immune-deficient mice followed by adoptive transfer of human PBMC led to the invasion of diverse T-cell subsets. Single cell transcriptomic analysis revealed that stromal cells in the organoids upregulated expression of immune response genes upon immune cell invasion. Moreover, immune regulatory PD-L1 protein was elevated in epithelial cells while genes related to nephron differentiation and function were downregulated. This study characterized the interaction between immune cells and kidney organoids, which will advance the use of kidney organoids for transplantation research.
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Transplante de Rim , Rim , Organoides , Humanos , Organoides/imunologia , Animais , Rim/imunologia , Camundongos , Técnicas de Cocultura , Leucócitos Mononucleares/imunologia , Células-Tronco Pluripotentes Induzidas/citologia , Linfócitos T/imunologia , Sistema Imunitário , Antígeno B7-H1/metabolismo , Macrófagos/imunologiaRESUMO
Healthy individuals with hybrid immunity, due to a SARS-CoV-2 infection prior to first vaccination, have stronger immune responses compared to those who were exclusively vaccinated. However, little is known about the characteristics of antibody, B- and T-cell responses in kidney disease patients with hybrid immunity. Here, we explored differences between kidney disease patients and controls with hybrid immunity after asymptomatic or mild coronavirus disease-2019 (COVID-19). We studied the kinetics, magnitude, breadth and phenotype of SARS-CoV-2-specific immune responses against primary mRNA-1273 vaccination in patients with chronic kidney disease or on dialysis, kidney transplant recipients, and controls with hybrid immunity. Although vaccination alone is less immunogenic in kidney disease patients, mRNA-1273 induced a robust immune response in patients with prior SARS-CoV-2 infection. In contrast, kidney disease patients with hybrid immunity develop SARS-CoV-2 antibody, B- and T-cell responses that are equally strong or stronger than controls. Phenotypic analysis showed that Spike (S)-specific B-cells varied between groups in lymph node-homing and memory phenotypes, yet S-specific T-cell responses were phenotypically consistent across groups. The heterogeneity amongst immune responses in hybrid immune kidney patients warrants further studies in larger cohorts to unravel markers of long-term protection that can be used for the design of targeted vaccine regimens.
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Purpose: Kidney transplantation is the optimal treatment for patients with end-stage kidney disease. Donor-specific urinary extracellular vesicles (uEVs) hold potential as biomarkers for assessing allograft status. We aimed to develop a method for identifying donor-specific uEVs based on human leukocyte antigen (HLA) mismatching with the kidney transplant recipients (KTRs). Patients and Methods: Urine and plasma were obtained from HLA-A2+ donors and HLA-A2- KTRs pre-transplant. CD9 (tetraspanin, EV marker) and HLA-A2 double-positive (CD9+ HLA-A2+) EVs were quantified using isolation-free imaging flow cytometry (IFCM). Healthy individuals' urine was used to investigate CD9+ HLA-class-I+ uEV quantification using IFCM, time-resolved fluoroimmunoassay (TR-FIA), and immunogold staining cryo-electron microscopy (cryo-EM). Culture-derived CD9+ HLA-class-I+ EVs were spiked into the urine to investigate urine matrix effects on uEV HLA detection. Deceased donor kidneys and peritumoral kidney tissue were used for HLA class I detection with histochemistry. Results: The concentrations of CD9+ HLA-A2+ EVs in both donor and recipient urine approached the negative (detergent-treated) control levels for IFCM and were significantly lower than those observed in donor plasma. In parallel, universal HLA class I+ uEVs were similarly undetectable in the urine and uEV isolates compared with plasma, as verified by IFCM, TR-FIA, and cryogenic electron microscopy. Culture supernatant containing HLA class I+ vesicles from B, T, and human proximal tubule cells were spiked into the urine, and these EVs remained stable at 37°C for 8 hours. Immunohistochemistry revealed that HLA class I was predominantly expressed on the basolateral side of renal tubules, with limited expression on their urine/apical side. Conclusion: The detection of donor-specific uEVs is hindered by the limited release of HLA class I+ EVs from the kidney into the urine, primarily due to the polarized HLA class I expression on renal tubules. Identifying donor-specific uEVs requires further advancements in recognizing transplant-specific uEVs and urine-associated markers.
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Vesículas Extracelulares , Antígeno HLA-A2 , Humanos , Microscopia Crioeletrônica , Antígeno HLA-A2/metabolismo , Vesículas Extracelulares/metabolismo , Rim , Biomarcadores/metabolismoRESUMO
BACKGROUND: Machine perfusion is the preferred preservation method for deceased donor kidneys. Perfusate fluid, which contains a complex mixture of components, offers potential insight into the organ's viability and function. This study explored immune cell release, particularly tissue-resident lymphocytes (TRLs), during donor kidney machine perfusion and its correlation with injury markers. METHODS: Perfusate samples from hypothermic machine perfusion (HMP; nâ =â 26) and normothermic machine perfusion (NMP; nâ =â 16) of human donor kidneys were analyzed for TRLs using flow cytometry. Residency was defined by expressions of CD69, CD103, and CD49as. TRL release was quantified exclusively in NMP. Additionally, levels of cell-free DNA, neutrophil gelatinase-associated lipocalin, and soluble E-cadherin (sE-cadherin) were measured in NMP supernatants with quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: Both HMP and NMP samples contained a heterogeneous population of TRLs, including CD4 + tissue-resident memory T cells, CD8 + tissue-resident memory T cells, tissue-resident natural killer cells, tissue-resident natural killer T cells, and helper-like innate lymphoid cells. Median TRL proportions among total CD45 + lymphocytes were 0.89% (NMP) and 0.84% (HMP). TRL quantities in NMP did not correlate with donor characteristics, perfusion parameters, posttransplant outcomes, or cell-free DNA and neutrophil gelatinase-associated lipocalin concentrations. However, CD103 + TRL release positively correlated with the release of sE-cadherin, the ligand for the CD103 integrin. CONCLUSIONS: Human donor kidneys release TRLs during both HMP and NMP. The release of CD103 + TRLs was associated with the loss of their ligand sE-cadherin but not with general transplant injury biomarkers.
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Antígenos CD , Transplante de Rim , Rim , Lipocalina-2 , Preservação de Órgãos , Perfusão , Humanos , Transplante de Rim/métodos , Perfusão/métodos , Masculino , Pessoa de Meia-Idade , Feminino , Lipocalina-2/metabolismo , Lipocalina-2/análise , Adulto , Preservação de Órgãos/métodos , Antígenos CD/metabolismo , Rim/imunologia , Rim/irrigação sanguínea , Doadores de Tecidos , Linfócitos/imunologia , Linfócitos/metabolismo , Biomarcadores/metabolismo , Caderinas/metabolismo , Idoso , Cadeias alfa de Integrinas/metabolismo , Citometria de Fluxo , Lipocalinas/metabolismo , Hipotermia InduzidaRESUMO
The extent to which tissue-resident memory T (TRM) cells in transplanted organs possess alloreactivity is uncertain. This study investigates the alloreactive potential of TRM cells in kidney explants from 4 patients who experienced severe acute rejection leading to graft loss. Alloreactive T cell receptor (TCR) clones were identified in pretransplant blood samples through mixed lymphocyte reactions, followed by single-cell RNA and TCR sequencing of the proliferated recipient T cells. Subsequently, these TCR clones were traced in the TRM cells of kidney explants, which were also subjected to single-cell RNA and TCR sequencing. The proportion of recipient-derived TRM cells expressing an alloreactive TCR in the 4 kidney explants varied from 0% to 9%. Notably, these alloreactive TCRs were predominantly found among CD4+ and CD8+ TRM cells with an effector phenotype. Intriguingly, these clones were present not only in recipient-derived TRM cells but also in donor-derived TRM cells, constituting up to 4% of the donor population, suggesting the presence of self-reactive TRM cells. Overall, our study demonstrates that T cells with alloreactive potential present in the peripheral blood prior to transplantation can infiltrate the kidney transplant and adopt a TRM phenotype.
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Rejeição de Enxerto , Transplante de Rim , Células T de Memória , Humanos , Células T de Memória/imunologia , Rejeição de Enxerto/imunologia , Masculino , Feminino , Memória Imunológica , Pessoa de Meia-Idade , Sobrevivência de Enxerto/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Adulto , Prognóstico , Seguimentos , Linfócitos T CD8-Positivos/imunologia , Falência Renal Crônica/cirurgia , Falência Renal Crônica/imunologia , Doadores de TecidosRESUMO
Allogeneic transplant organs are potentially highly immunogenic. The endothelial cells (ECs) located within the vascular system serve as the primary interface between the recipient's immune system and the donor organ, playing a key role in the alloimmune response. In this study, we investigated the potential use of recipient-derived ECs in a vein recellularization model. In this study, human iliac veins underwent complete decellularization using a Triton X-100 protocol. We demonstrated the feasibility of re-endothelializing acellular blood vessels using either human umbilical cord vein endothelial cell or human venous-derived ECs, with this re- endothelialization being sustainable for up to 28 days in vitro. The re-endothelialized veins exhibited the restoration of vascular barrier function, along with the restoration of innate immunoregulatory capabilities, evident through the facilitation of monocytic cell transmigration and their polarization toward a macrophage phenotype following transendothelial extravasation. Finally, we explored whether recellularization with EC of a different donor could prevent antibody-mediated rejection. We demonstrated that in chimeric vessels, allogeneic EC became a target of the humoral anti-donor response after activation of the classical immune complement pathway whereas autologous EC were spared, emphasizing their potential utility before transplantation. In conclusion, our study demonstrates that replacement of EC in transplants could reduce the immunological challenges associated with allogeneic grafts.
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Quimerismo , Células Endoteliais , Humanos , Endotélio VascularRESUMO
Kidney transplant (KTx) biopsies showing transplant glomerulopathy (TG) (glomerular basement membrane double contours (cg) > 0) and microvascular inflammation (MVI) in the absence of C4d staining and donor-specific antibodies (DSAs) do not fulfill the criteria for chronic active antibody-mediated rejection (CA-AMR) diagnosis and do not fit into any other Banff category. To investigate this, we initiated a multicenter intercontinental study encompassing 36 cases, comparing the immunomic and transcriptomic profiles of 14 KTx biopsies classified as cg+MVI DSA-/C4d- with 22 classified as CA-AMR DSA+/C4d+ through novel transcriptomic analysis using the NanoString Banff-Human Organ Transplant (B-HOT) panel and subsequent orthogonal subset analysis using two innovative 5-marker multiplex immunofluorescent panels. Nineteen genes were differentially expressed between the two study groups. Samples diagnosed with CA-AMR DSA+/C4d+ showed a higher glomerular abundance of natural killer cells and higher transcriptomic cell type scores for macrophages in an environment characterized by increased expression of complement-related genes (i.e., C5AR1) and higher activity of angiogenesis, interstitial fibrosis tubular atrophy, CA-AMR, and DSA-related pathways when compared to samples diagnosed with cg+MVI DSA-/C4d-. Samples diagnosed with cg+MVI DSA-/C4d- displayed a higher glomerular abundance and activity of T cells (CD3+, CD3+CD8+, and CD3+CD8-). Thus, we show that using novel multiomic techniques, KTx biopsies with cg+MVI DSA-/C4d- have a prominent T-cell presence and activity, putting forward the possibility that these represent a more T-cell dominant phenotype.
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Nefropatias , Transplante de Rim , Humanos , Multiômica , Isoanticorpos , Linfócitos T , Transplante de Rim/efeitos adversos , Inflamação , Biópsia , Rejeição de Enxerto , Fragmentos de Peptídeos , Complemento C4bRESUMO
Tissue-resident lymphocytes (TRLs) are critical for local protection against viral pathogens in peripheral tissue. However, it is unclear if TRLs perform a similar role in transplanted organs under chronic immunosuppressed conditions. In this study, we aimed to characterize the TRL compartment in human kidney transplant nephrectomies and examine its potential role in antiviral immunity. The TRL compartment of kidney transplants contained diverse innate, innate-like, and adaptive TRL populations expressing the canonical residency markers CD69, CD103, and CD49a. Chimerism of donor and recipient cells was present in 43% of kidney transplants and occurred in all TRL subpopulations. Paired single-cell transcriptome and T cell receptor (TCR) sequencing showed that donor and recipient tissue-resident memory T (TRM) cells exhibit striking similarities in their transcriptomic profiles and share numerous TCR clonotypes predicted to target viral pathogens. Virus dextramer staining further confirmed that CD8 TRM cells of both donor and recipient origin express TCRs with specificities against common viruses, including CMV, EBV, BK polyomavirus, and influenza A. Overall, the study results demonstrate that a diverse population of TRLs resides in kidney transplants and offer compelling evidence that TRM cells of both donor and recipient origin reside within this TRL population and may contribute to local protection against viral pathogens.
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Transplante de Rim , Vírus , Humanos , Memória Imunológica , Linfócitos T CD8-Positivos , Receptores de Antígenos de Linfócitos TRESUMO
Solid organ transplant recipients (SOTRs) are at high risk of human herpesvirus (HHV)-related morbidity and mortality due to the use of immunosuppressive therapy. We aim to increase awareness and understanding of HHV disease burden in SOTRs by providing an overview of current prevention and management strategies as described in the literature and guidelines. We discuss challenges in both prevention and treatment as well as future perspectives.
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Herpes Simples , Infecções por Herpesviridae , Herpesvirus Humano 6 , Transplante de Órgãos , Humanos , Transplante de Órgãos/efeitos adversos , Infecções por Herpesviridae/tratamento farmacológico , Infecções por Herpesviridae/prevenção & controle , TransplantadosRESUMO
T-cell-mediated help to B cells is required for the development of humoral responses, in which the cytokine interleukin (IL)-21 is key. Here, we studied the mRNA-1273 vaccine-induced SARS-CoV-2-specific memory T-cell IL-21 response, memory B cell response, and immunoglobulin (Ig)G antibody levels in peripheral blood at 28 days after the second vaccination by ELISpot and the fluorescent bead-based multiplex immunoassay, respectively. We included 40 patients with chronic kidney disease (CKD), 34 patients on dialysis, 63 kidney transplant recipients (KTR), and 47 controls. We found that KTR, but not patients with CKD and those receiving dialysis, showed a significantly lower number of SARS-CoV-2-specific IL-21 producing T cells than controls (P < .001). KTR and patients with CKD showed lower numbers of SARS-CoV-2-specific IgG-producing memory B cells when compared with controls (P < .001 and P = .01, respectively). The T-cell IL-21 response was positively associated with the SARS-CoV-2-specific B cell response and the SARS-CoV-2 spike S1-specific IgG antibody levels (both Pearson r = 0.5; P < .001). In addition, SARS-CoV-2-specific B cell responses were shown to be IL-21 dependent. Taken together, we show that IL-21 signaling is important in eliciting robust B cell-mediated immune responses in patients with kidney disease and KTR.
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COVID-19 , Nefropatias , Transplante de Rim , Humanos , Vacinas contra COVID-19 , Vacina de mRNA-1273 contra 2019-nCoV , SARS-CoV-2 , Interleucinas , Imunoglobulina G , Anticorpos Antivirais , Imunidade , TransplantadosRESUMO
Cytokines are regulators of the immune response against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, the contribution of cytokine-secreting CD4+ and CD8+ memory T cells to the SARS-CoV-2-specific humoral immune response in immunocompromised kidney patients is unknown. Here, we profiled 12 cytokines after stimulation of whole blood obtained 28 days post second 100 µg mRNA-1273 vaccination with peptides covering the SARS-CoV-2 spike (S)-protein from patients with chronic kidney disease (CKD) stage 4/5, on dialysis, kidney transplant recipients (KTR), and healthy controls. Unsupervised hierarchical clustering analysis revealed two distinct vaccine-induced cytokine profiles. The first profile was characterized by high levels of T-helper (Th)1 (IL-2, TNF-α, and IFN-γ) and Th2 (IL-4, IL-5, IL-13) cytokines, and low levels of Th17 (IL-17A, IL-22) and Th9 (IL-9) cytokines. This cluster was dominated by patients with CKD, on dialysis, and healthy controls. In contrast, the second cytokine profile contained predominantly KTRs producing mainly Th1 cytokines upon re-stimulation, with lower levels or absence of Th2, Th17, and Th9 cytokines. Multivariate analyses indicated that a balanced memory T cell response with the production of Th1 and Th2 cytokines was associated with high levels of S1-specific binding and neutralizing antibodies mainly at 6 months after second vaccination. In conclusion, seroconversion is associated with the balanced production of cytokines by memory T cells. This emphasizes the importance of measuring multiple T cell cytokines to understand their influence on seroconversion and potentially gain more information about the protection induced by vaccine-induced memory T cells.
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Memory T cells are important mediators of transplant rejection but are not routinely measured before or after kidney transplantation. The aims of this study were as follows: (1) validate whether pretransplant donor-reactive memory T cells are reliable predictors of acute rejection (AR) (2) determine whether donor-reactive memory T cells can distinguish AR from other causes of transplant dysfunction. Methods: Samples from 103 consecutive kidney transplant recipients (2018-2019) were obtained pretransplantation and at time of for-cause biopsy sampling within 6 mo of transplantation. The number of donor-reactive interferon gamma (IFN-γ) and interleukin (IL)-21-producing memory T cells was analyzed by enzyme-linked immunosorbent spot (ELISPOT) assay. Results: Of the 63 patients who underwent a biopsy, 25 had a biopsy-proven acute rejection (BPAR; 22 aTCMR and 3 aAMR), 19 had a presumed rejection, and 19 had no rejection. Receiver operating characteristic analysis showed that the pretransplant IFN-γ ELISPOT assay distinguished between patients who later developed BPAR and patients who remained rejection-free (area under the curve [AUC] 0.73; sensitivity 96% and specificity 41%). Both the IFN-γ and IL-21 assays were able to discriminate BPAR from other causes of transplant dysfunction (AUC 0.81; sensitivity 87% and specificity 76% and AUC 0.81; sensitivity 93% and specificity 68%, respectively). Conclusions: This study validates that a high number of donor-reactive memory T cells before transplantation is associated with the development of AR after transplantation. Furthermore, it demonstrates that the IFN-γ and IL-21 ELISPOT assays are able to discriminate between patients with AR and patients without AR at the time of biopsy sampling.
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Mast cells are potential contributors to chronic changes in kidney transplants (KTx). Here, the role of mast cells (MCs) in KTx is investigated in patients with minimal inflammatory lesions. Methods: Fourty-seven KTx biopsies (2009-2018) with borderline pathological evidence for T cell-mediated rejection according to the Banff'17 Update were retrospectively included and corresponding clinical data was collected. Immunohistochemistry for tryptase was performed on formalin-fixed paraffin-embedded sections. Cortical MCs were counted and corrected for area (MC/mm²). Interstitial fibrosis was assessed by Sirius Red staining and quantified using digital image analysis (QuPath). Results: Increased MC number was correlated to donor age (spearman's r = 0.35, P = 0.022), deceased donor kidneys (mean difference = 0.74, t [32.5] = 2.21, P = 0.035), and delayed graft function (MD = 0.78, t [33.9] = 2.43, P = 0.020). Increased MC number was also correlated to the amount of interstitial fibrosis (r = 0.42, P = 0.003) but did not correlate with transplant function over time (r = -0.14, P = 0.36). Additionally, transplant survival 2 y post-biopsy was not correlated to MC number (mean difference = -0.02, t [15.36] = -0.06, P = 0.96). Conclusions: MC number in suspicious (borderline) for acute T cell-mediated rejection is correlated to interstitial fibrosis and time post-transplantation, suggesting MCs to be a marker for cumulative burden of tissue injury. There was no association between MCs and transplant function over time or transplant survival 2 y post-biopsy. It remains unclear whether MCs are just a bystander or have pro-inflammatory or anti-inflammatory effects in the KTx with minimal lesions.
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BACKGROUND: Potentially harmful nonhuman leukocyte antigen antibodies have been identified in renal transplantation, including natural immunoglobulin G antibodies (Nabs) reactive to varied antigenic structures, including apoptotic cells. METHODS: In this retrospective, multicenter study, we assessed Nabs by reactivity to apoptotic cells in sera collected from 980 kidney transplant recipients across 4 centers to determine their association with graft outcomes. RESULTS: Elevated pretransplant Nabs were associated with graft loss (hazard ratio [HR] 2.71; 95% confidence interval [CI], 1.15-6.39; P = 0.0232), the composite endpoint of graft loss or severe graft dysfunction (HR 2.40; 95% CI, 1.13-5.10; P = 0.0232), and T cell-mediated rejection (odds ratio [OR] 1.77; 95% CI, 1.07-3.02; P = 0.0310). High pretransplant Nabs together with donor-specific antibodies (DSAs) were associated with increased risk of composite outcomes (HR 6.31; 95% CI, 1.81-22.0; P = 0.0039). In patients with high pretransplant Nabs, the subsequent development of posttransplant Nabs was associated with both T cell-mediated rejection (OR 3.64; 95% CI, 1.61-8.36; P = 0.0021) and mixed rejection (OR 3.10; 95% CI, 1.02-9.75; P = 0.0473). Finally, elevated pre- and posttransplant Nabs combined with DSAs were associated with increased risk of composite outcomes (HR 3.97; 95% CI, 1.51-10.43; P = 0.0052) and T cell-mediated rejection (OR 7.28; 95% CI, 2.16-25.96; P = 0.0016). CONCLUSIONS: The presence of pre- and posttransplant Nabs, together with DSAs, was associated with increased risk of poor graft outcomes and rejection after renal transplantation.