bluuebunny/crossref_metadata_2025_split huggingface dataset:
#2585 Human kidneys house innate-like B cells that transcriptomically mirror murine B-1 cells and change with age
Authors: Suchanek Ondrej , Stewart Benjamin , Richoz Nathan , Clatworthy Menna R 
Published: May 2024

Abstract

Background and Aims
There is growing evidence that B cells (memory and innate-like) reside in non-lymphoid organs where they play an important role for generating local immune responses or maintaining tolerance [1]. Several studies observed accumulation of innate-like self-reactive B cells in human kidneys following an injury or transplant rejection, associated with progressive organ dysfunction [2,3]. However, the origin of these B cells is unknown. Here, were investigated whether human kidneys house B cells in homeostasis and how they change with donor age.

Method
We examined the number, phenotype and clonality of B cells in human kidneys that were perfused to remove circulating cells, and in matched splenic tissue obtained from the same transplant donor (N = 19, median age 56 years (range: 18–80). Suspensions from homogenized organs were analyzed using a 35-marker mass cytometry panel and single-cell RNA sequencing. B cells were also sorted for bulk BCR-sequencing.

Results
At steady state, human kidneys house B cells enriched for non-naïve (CD27+IgD− and double-negative) subsets when compared to spleen or younger donors. The renal cortex harbours ten times more B cells per gram of tissue than medulla. In contrast to spleen, B cell count and B:T cell ratio in renal cortex significantly increase with age (Fig. A). Kidney B-cell immune repertoire is less diverse but also less mutated than spleen, suggesting the presence of innate-like B cells. Indeed, single-cell-RNA sequencing analysis reveals that large proportion of non-naïve kidney B cells belongs to IgM/IgA memory subset with transcriptomic similarity to murine B-1 cells (not marginal-zone B cells) (Fig. B).

Conclusion
Our study shows that under homeostatic conditions, human kidneys harbour a large proportion of IgM/IgA memory B cells with innate-like features that transcriptomically mirror murine B-1 cells and increase with age. This B cell subset might further expand following an injury and fuel local immunopathology and organ dysfunction as observed by previous studies [2,3]. Hence, selective targeting of these innate-like B cells could be an important therapeutic strategy.
#2906 Kidney immune cells and endothelial cells can be modulated by low-salt and high-salt diets
Authors: Jang Minyoung , Kim Jeongyun , Jeong Seoin , Jeon Junseok , Jeon Hojin , Lee Jung Eun , Huh Wooseong , Jang Hye Ryoun , Lee Kyungho 
Published: May 2024

Abstract

Background and Aims
Kidney immune cells and endothelial cells are involved in pathogenesis of kidney ischemia-reperfusion injury and potential therapeutic targets to improve kidney transplant outcomes. We hypothesized that dietary salt intake can change kidney immune cells and endothelial cells.

Method
C57BL/6 mice were treated with normal diet, low-salt diet, or high-salt diet. After 6 weeks of allocated diets, mice were euthanized, and their kidneys were collected. Leukocyte infiltration was assessed with CD45 immunohistochemistry. Lymphocytes were isolated from kidneys and were studied by flow cytometry. Human kidney transplant tissues obtained by a protocol biopsy at 2 weeks after kidney transplantation were stained with CD45, CD3, CD20, and CD31. Expression of each marker was quantified using an automated imaging analysis system and analyzed per donors’ pre-donation 24 h urine sodium levels. Induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from healthy individuals and end-stage kidney disease (ESKD) patients were treated with different sodium concentrations, and their proliferation was assessed.

Results
Kidneys from mice fed with high-salt diet had higher kidney leukocytes (CD45+) than those fed with normal diet (1.9 ± 0.3% vs 0.9 ± 0.1%, P = .043). Effector-memory CD4+ T cells (normal 44.2 ± 2.6%; low-salt 57.1 ± 3.5%, P = .020; high-salt 62.1 ± 2.5% of CD4+ T cells, P = .002) and mature B cells (70.0 ± 1.5%; 79.1 ± 1.4%, P = .001; 76.7 ± 1.6% of CD19+ cells, P = .015) increased by low-salt and high-salt diets, whereas naïve CD4+ T cells deceased (45.9 ± 2.1%; 32.7 ± 3.2%, P = .016; 27.8 ± 3.1% of CD4+ T cells, P = .001) in kidneys. Human kidney transplants from donors under low-salt diet showed lower total leukocytes (CD45+, 0.3 ± 0.1% vs 0.9 ± 0.3%, P = .019) with lower T and B cells (CD3+, 1.8 ± 0.2% vs 3.5 ± 0.4%, P&lt;.001; CD20+, 0.8 ± 0.1% vs 2.1 ± 0.6%, P = .011) and higher capillary density (CD31+, 29.0 ± 2.2% vs 16.1 ± 1.8%, P = .009) compared to those from donors under high-salt diet. The proliferation of iPSC-ECs from healthy individuals and ESKD patients after hypoxia was reduced under higher sodium concentrations.

Conclusion
High-salt and low-salt diets affect kidney immune cell compositions and numbers as well as endothelial cells. Reconstitution of kidney microenvironment by modifying dietary salt intake could be a novel approach to improve kidney transplant outcomes.
#2461 KIR-HLA-I genetic mismatch and the development of antibody-mediated rejection and microvascular inflammation after renal transplantation
Authors: Federico-Vega Judith , Alari-Pahissa Elisenda , Bello Victor , Buxeda Anna , Gimeno Javier , Sanz-Ureña Sara , Medina-Jaramillo Andrea , Redondo-Pachón Dolores , Pérez-Sáez Maria José , Vilches Carlos , López-Botet Miguel , Crespo Marta 
Published: May 2024

Abstract

Background and Aims
Antibody-mediated rejection (ABMR) and microvascular inflammation (MVI) contribute to kidney transplant (KT) loss of function. The contribution of Natural Killer (NK) cells to the development of ABMR/MVI through inhibitory (iKIR) and activating (aKIR) HLA-I KIR (Killer-cell Immunoglobulin-like Receptors) has been proposed. The presence of an iKIR gene in the KT recipient (KTR) recognizing a self HLA-I ligand absent in the donor is defined as an iKIR-HLA-I mismatch (MM), and the presence of an aKIR gene in the KTR with HLA-I ligand in the graft absent in the KTR is defined as an aKIR-HLA-I MM. These MMs indicate the presence of potentially alloreactive NK cells that could contribute to the graft rejection, especially in the presence of NK receptor activating ligands or DSA. Our aim was to study the relationship between the number of KIR-HLA-I mismatches and ABMR/MVI.

Method
We selected 56 first KT, not treated with thymoglobulin or rituximab: 24 cases with ABMR/MVI and 32 controls without rejection in biopsies at 12-36 months. Donor and recipient HLA-I genotypes were determined by NGS, and recipient KIR genotypes by PCR-SSO (Luminex). The interactions considered were: KIR2DL1/HLA-C2, KIR2DL2&KIR2DL3/HLA-C1, KIR3DL1/HLA-Bw4, KIR3DL2/HLA-A*03, A*11, KIR2DS1/HLA-C2, KIR2DS2/HLA-C1, KIR3DS1/HLA-Bw4-I80 and KIR2DS4/HLA-A*11, C*02, C*04, C*05, C*16:01.

Results
KT recipients had a mean age of 54.55 years, 30.36% female and 8.92% living donor with no significant differences between ABMR/MVI and controls. The proportion of patients with ≥1 iKIR-HLA-I MM was higher in the ABMR/MVI group compared to controls (75% vs 56.25%, P = .1473), with a significant difference in the percentage of KIR3DL1 MM (29.17% vs 6.25%, P = .0296). The proportion of patients with at least one aKIR-HLA-I MM was non-significantly lower in ABMR/MVI compared to the control group (20.83% vs 28.13%, P = .5329). Overall, the proportion of KT recipients with ≥1 MM, either iKIR or aKIR, was 21% higher in the ABMR/MVI group (83.33% vs 68.75%, P = .2123).

Conclusion
In a population of immunologically low-risk KT recipients, we found a significantly greater proportion of patients with genetic iKIR-HLA-I MM in those with ABMR/MVI, but not of aKIR-HLA-I MM. NK cells with iKIR-HLA-I MM could contribute to antibody-mediated allograft damage together with other mechanisms.
#801 Impact of delayed graft function on cardiovascular events in kidney transplant recipients
Authors: Beaudrey Thomas , Aymes Estelle , Thaunat Olivier , Group Spiesser , Consortium Divat , Giral Magali , Ohlmann Sophie , Hamroun Aghiles , Florens Nans 
Published: May 2024

Abstract

Background and Aims
Acute kidney injury (AKI) increases long-term cardiovascular risk in non-transplanted patients. Delayed graft function (DGF) mimics AKI in kidney transplant recipients, yet its impact on their cardiovascular risk remains unclear.

Method
We investigated the impact of DGF on cardiovascular morbidity and mortality in kidney transplant recipients using data from patients across 17 French centres from the Astre and Divat cohorts. Included patients were aged 18 years or older, transplanted between 2008 and 2022, with follow-up until 31/03/2023. DGF was defined as the need for hemodialysis within the first week following renal transplantation. The primary outcome was the impact of DGF on the occurrence of a cardiovascular event (composite endpoint including cardiovascular death, coronary artery disease, stroke, heart failure), adjusted for conventional cardiovascular risk factors and glomerular filtration rate at 3 months. Analyses were performed using univariate and multivariate Cox models.

Results
Among the 19, 837 patients transplanted during the inclusion period, 3, 794 experienced DGF (19.1%). In the multivariate Cox model, DGF was strongly associated with cardiovascular risk (adjusted Hazard Ratio [HR] = 1.37, P &lt; .0001), independently of renal function. Other significantly associated variables included age, duration of dialysis, expanded criteria donors, diabetes, dyslipidemia, smoking, initial nephropathy, and various cardiovascular comorbidities. The effect of DGF was predominantly observed in men, patients over 40, and those at lower cardiovascular risk. DGF was associated with independent cardiac outcomes, such as cardiovascular death (HR 1.31), coronaropathy (HR 1.51), heart failure (HR 1.61 and arrhythmia (HR 1.38), but not with stroke (HR 0.99) nor peripheral artery disease (HR 0.97).

Conclusion
DGF is an independent risk factor for the occurrence of cardiovascular events in kidney transplant recipients. Strategies aimed at minimizing DGF could potentially reduce cardiovascular complications in these patients.
#1237 Management of dyslipidaemia with evolocumab in kidney transplant recipients
Authors: Amaro José Manuel , Villanego Florentino , Chavez Cristhian Orellana , Vigara Luis Alberto , Alonso Marta , García Álvarez Teresa , Blanca María Auxiliadora Mazuecos 
Published: May 2024

Abstract

Background and Aims
Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have shown to reduce major adverse cardiovascular events in very-high cardiovascular risk patients, even with chronic kidney disease. However, the experience is very scarce in kidney transplant (KT) recipients.

Method
We performed a prospective cohort study of KT recipients who started evolocumab in our hospital (15/09/22–11/05/23) and were followed during at least 6 months. The criteria for its prescription were not achieving therapeutic c-LDL goals despite high-potency statins and ezetimibe treatment or adverse effects of statins (myalgias, hypertransaminasemia). Total cholesterol, c-LDL, triglycerides, estimated glomerular filtration rate (eGFR) and albuminuria were compared at baseline, 1st, 3rd and 6th month after starting the treatment. We also collected drug-related adverse effects and immunosuppressive trough levels.

Results
In this period, 13 KT started evolocumab. Previous lipid-lowering treatments were maintained. Mean KT vintage was 32.4 months and 69.2% had personal history of ischemic heart disease. Median follow-up was 7 months.
Mean baseline c-LDL was 102.9 mg/dL and eGFR was 49 mL/min/m2. In the 3rd month after starting the treatment, we observed a reduction in cholesterol and c-LDL (p = 0.008, p = 0.009), which was maintained at 6 months (p &lt; 0.001, p = 0.002). However, no differences were found in triglycerides, eGFR, albuminuria and plasma immunosuppressants levels (Fig. 1). No cases of acute rejection or adverse effects were reported. In 5 patients, anti-HLA antibodies were determined as a part of their routine follow-up 6 months after the drug prescription and were negative.

Conclusion
In our experience, we observed good results with evolocumab, since total cholesterol and c-LDL reduced rapidly after starting the treatment. Furthermore, renal function maintained stable, no change in proteinuria and no other safety concerns were reported.
In our case, neither tacrolimus nor everolimus trough levels remained unchanged and no immunological adverse outcomes were notified.
More studies in this population and with longer follow-up are needed to assess the benefit on KT recipients and graft survival.
#2562 Effect of rituximab on post-transplant outcome in highly sensitized patients
Authors: Abdullaev Sherzod , Igamberdieva Ranokhon 
Published: May 2024

Abstract

Background and Aims
Pre-transplant sensitization is important risk factor for the development of antibody-mediated rejection (ABMR) and can result in inferior long-term allograft survival in kidney transplantation (KT). The aim of this study was to investigate the effect of pre-transplant Rituximab infusion on the clinical outcome in highly sensitized patients.

Method
The study included 128 consecutive recipients who received renal transplant between 05/2022 and 12/2023, of them 68 patients showed the result of panel-reactive antibody higher than 30%, but showed negative crossmatch test before transplantation. Out of them, 44 patients who took pre-transplant Rituximab at a dose of 375 mg/m2 belonged to Rituximab group and remained 24 patients were regarded as control group. We compared the development of ABMR, the change of allograft function and allograft survival rate between 2 groups after KT.

Results
Between two groups, no difference was found in baseline characteristics such as age at KT, gender, pre-transplant dialysis duration, primary renal disease. The mean value of PRA and HLA mismatching number, the type of main immunosuppressive agent did not differ as well. After KT, the development of ABMR was significantly lower in Rituximab group (5/44 (11.4%)) compared to control group (10/24 (41.7%), p &lt; 0.005) and total rejection rate showed lower tendency in Rituximab group as well (p = 0.052). However, the incidence of CMV, fungal or bacterial infections was similar between the groups. Allograft function assessed by MDRD eGFR at 14 days after KT was significantly higher in Rituximab group compared to control group, but at 6 and 12 months from KT, it did not differ between two groups. Allograft rejection free survival was significantly higher in Rituximab group compared to control group (p &lt; 0.05).

Conclusion
In sensitized patients with high PRA but negative crossmatch, Rituximab was effective to prevent the development of ABMR without an increased incidence of opportunistic infections.
#3052 mTOR inhibitors in kidney transplant recipients with high immunological risk: practical insights from clinical experience
Authors: Cacho Judit , Cassia Matthias , Torres Veronica , Pérez Hugo Vergara , González Ángela , Rodríguez Diana , Montagud-Marrahi Enrique , Cuadrado Elena , Diekmann Fritz , Cucchiari David 
Published: May 2024

Abstract

Background and Aims
The use of mTOR inhibitors (mTORi) is not usually considered in high immunological risk kidney transplant recipients (KTR) for a perceived increased risk of rejection. However, in most of the studies that examined the combination of mTORi with calcineurin inhibitors (CNI), hypersensitized patients have been excluded from enrollment. The aim of the present study is to analyze our clinical experience with the use of mTORi in association with calcineurin inhibitors (CNI) in this subset of patients.

Method
Analysis of 212 consecutive kidney transplant recipients with a baseline calculated panel reactive antibody (cPRA) ≥50% who received a graft from June 2013 to December 2019. Immunosuppression was based on tacrolimus, steroids and, alternatively, mycophenolic acid (MPA; n = 96) or mTORi (either sirolimus or everolimus, target trough levels 3-8 ng/ml, n = 116) depending on the active Institution's protocol at the time of transplantation. The outcomes chosen included rejection-free, graft and patient survival and were analyzed by means of Cox-regression analysis.

Results
Demographic and immunological characteristics were similar between groups, apart from the higher number of living donors in the MPA group (42.7% vs 14.7%%, P &lt; 0.001). Baseline cPRA was 92.5 [76-98]% for the MPA and 94 [77.25-98]% for the mTORi group, respectively (P = 0.882). Induction therapy with lymphocyte-depleting agents was employed in the majority of patients (91.7% in the MPA group and 88.8% in the mTORi group, P = 0.898). Median follow-up time was 2.6 [1.45-4.05] years. Biopsy-proven rejection (either cellular or humoral) occurred in 33.3% of the MPA and in 19.8% of the mTORi group, respectively. Cox-regression analysis of rejection-free survival revealed better rejection-free survival with mTORi versus MPA (HR [95% CI], 0.54 [0.32-0.98], P = 0.028). The only other baseline factor associated with rejection was previous transplantation (HR [95% CI] 1.96 [1.07-3.60], P = 0.030). When entered into a bivariable Cox-regression analysis, both mTORi and previous transplantation maintained a statistical significant association with rejection (mTORi versus MPA HR [95% CI] 0.53 [0.31-0.91], P = 0.023, and previous transplantation HR [95% CI] 2.01 [1.09-3.69], P = 0.024). No differences between mTORi and MPA were noted for graft (HR [95% CI] 0.90 [0.40-2.02], P = 0.807) and patient survival (HR [95% CI] 1.23 [0.60-2.50, P = 0.606). Median creatinine 1 year after transplantation was 1.45 [1.11-1.98]mg/dl for the MPA group and 1.51 [1.09-2.06]mg/dl for the mTORi group (P = 0.917).

Conclusion
This retrospective study suggests that hypersensitized KTRs can receive safely a maintenance immunosuppression based on a combination of CNI with mTORi, without an increased risk of rejection.
#580 Pitfalls in valganciclovir prophylaxis dose adjustment based on renal function in kidney transplant recipients
Authors: Hammer Nathalie , Hoessly Linard , Sidler Daniel , Neofytos Dionysios 
Published: May 2024

Abstract

Background
Clinically significant cytomegalovirus infection (csCMVi) is the most frequent viral infection in kidney transplant recipients (KTR). A daily dose of 900 mg valganciclovir (VGC) as primary antiviral prophylaxis (PAP) is frequently administered to KTR at risk for csCMVi, including CMV donor (D)+/recipient (R)− and CMV R+ patients after induction immunosuppression with thymoglobulin (R+/TG) until 6- and 3-months post-transplant, respectively. Dose adjustments for VGC are recommended based on renal function to reduce potential myelotoxicity. There is paucity of real-life data on VGC dose adjustment as PAP and association with clinical outcomes.

Method and Aims
Bicentric and retrospective Swiss Transplant Cohort Study (STCS)-embedded observational study including all consecutive adult D+/R− and R+/TG KTR between 2010 and 2020, who received PAP with VGC. The primary objective was to describe the proportion of VGC weekly entries, that was inappropriately (either under- or over-) dosed based on the associated renal function. Secondary objectives included the incidence of breakthrough csCMVi, potential associations between breakthrough-csCMVi and cytopenias with VGC dosing.

Results
Among 178 KTR included in both centres, 131 (73.6%) patients had at least two week entries for the longitudinal data of interest and were included in the outcome analysis. There were 1032 weekly VGC dose entries for 131 patients. Overall, 460 (44.6%) were appropriately dosed, while 234 (22.7%) and 338 (32.8%) were under- and over-dosed, respectively (Table 1). Inappropriate dosing was more frequent among R+/TG (133/214, 62.1%) than D+/R− (92/176, 52.3%, p = 0.05) during the first four weeks post-transplant. Nineteen (14.5%) patients had a breakthrough-csCMVi, without any association between breakthrough-csCMVi and VCG dosing (p = 0.44). Among cytopenias, there was no statistically significant difference in the proportion of weekly leucopenia, neutropenia, or thrombocytopenia values. In contrast, lymphopenia was more frequently observed when VGC was overdosed (p = 0.005, Table 2).

Conclusion
VGC as PAP in KTR is frequently inappropriately dosed, albeit without meaningful clinical associations, neither in terms of efficacy nor safety.
#623 One-year outcome of kidney transplant recipients harbouring complement regulatory gene mutation
Authors: Mittal Ankur , Konnur Abhijit , Gang Sishir , Hegde Umapati , Patel Hardik 
Published: May 2024

Abstract

Background and Aims
Thrombotic Microangiopathy (TMA) is associated with genetic abnormalities in complement regulatory pathways. The impact of complement regulatory gene (CRG) mutation on post-transplant TMA in Indian kidney transplant recipients (KTR) is unknown. This study was conducted to ascertain an association between post-transplant renal limited TMA and the risk of graft failure in KTRs harbouring mutations in genes encoding complement-regulatory proteins.

Method
A Single Centre, Prospective Cohort Study was undertaken to assess the incidence of post-transplant renal limited TMA in KTRs with mutations in genes encoding complement regulatory proteins. Patients enrolled over one year were followed up for one-year post-transplantation. Genetic testing was performed with MLPA and Clinical exome sequencing.

Results
138 KTRs with a mean age of 36.39 ± 12.39 years were enrolled. CRG mutation was seen in 96/138 (69.6%) KTRs. Duplication of the CFHR gene (n = 72) was most prevalent followed by mutations in CFH (n = 6), CFI (n = 2), MCP (n = 2), and DGKE (n = 1). Mutations in CFB, C3, and THBD genes were not detected. The Incidence of Post transplant renal limited TMA in KTRs with CRG mutations is 9.37% (9/96). Mutation related to aHUS was seen in 9 out of 11 patients who developed TMA. There was no significant difference in eGFR of patients with or without CRG mutation at the end of 1 year.

Conclusion
The prevalence of CRG mutation in KTRs is high and the majority of patients with post-transplant de novo TMA had CRG mutations. The graft functions at the end of 1 year were similar in patients with or without CRG gene mutation. This study suggests that the presence of CRG mutation should not preclude the option of Kidney transplantation in a patient with ESRD.