bluuebunny/crossref_metadata_2025 huggingface dataset:
#1121 Identification of kidney transcripts associated with prognosis in ANCA-associated glomerulonephritis
Authors: Brilland Benoit , Riou Jérémie , Boizard-Moracchini Andrea , Tortevoie Nathalie , Piccoli Giorgina , Assia Djema , Henry Nicolas , Copin Marie-Christine , Langlais David , Blanco Patrick , Delneste Yves , François Augusto Jean
Published: May 2024

Background and Aims

Kidney involvement in ANCA-associated vasculitis (AAV-GN) predicts poor patient and kidney survival. Deciphering the transcriptomic landscape in AAV-GN may provide insights into pathogenic mechanisms or identify biomarkers for refining diagnosis and/or prognosis, which would help stratify risk and tailor therapeutic management. We aimed to investigate the potential prognostic value of kidney transcripts associated with kidney survival.

Method

This study included adult patients with AAV-GN from the French Maine-Anjou Registry. Immune gene transcript analysis was performed on RNA extracted from 97 AAV-GN kidney biopsies using NanoString technology. Transcripts of interest were selected, and their prognostic performance was assessed with respect to current histological-based classifications. Following the identification of a possible role for clusterin (CLU), the relationship between serum CLU and prognosis was assessed.

Results

Among the 750 evaluated transcripts, we identified a 4-gene signature (XRCC6, PRKCD, TEK, and CLU) that was strongly associated with kidney survival (Fig. 1A). This signature predicted kidney survival better than histological-based classifications (global C-Index 0.87 vs. 0.65 for Berden classification or 0.81 for Renal Risk Score, with better time-dependent AUC and Brier scores, especially beyond 1 year after diagnosis) (Fig. 1B). Among these 4 transcripts, the expression level of the CLU transcript had the highest correlation with glomerular involvement, kidney function at diagnosis, and kidney survival. Serum CLU levels were associated with kidney survival, especially when assessed at 6 months from diagnosis (Fig. 1C, P = .023).

Conclusion

Transcriptomic analysis of kidney biopsies of AAV-GN identified potential transcripts that may improve prediction of kidney survival. This transcriptomic signature may help us gain a deeper understanding of the AAV-GN pathogenesis and provide insights for developing new therapeutic options.
#581 Therapeutic management of patients with GPA and MPA: a nationwide observational study in France
Authors: Bataille Pierre , Durel Cécile-Audrey , Thervet Eric , Chauveau Dominique , Maillet Serge , Schmidt Aurélie , Terrier Benjamin
Published: May 2024

Background and Aims

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are rare systemic necrotizing vasculitis. Treatment per rituximab was approved in 2013, and recent guidelines recommend corticosteroids sparing. A real-life pharmacoepidemiologic retrospective study was set up to describe the demographic characteristics of hospitalized GPA and MPA patients and compare the treatments of patients included before rituximab approval (over 2010–2012, Group 1) and after rituximab approval in France (over 2014–2017, Group 2).

Method

All adult patients hospitalized for GPA or MPA between January 1, 2010 and December 31, 2017 were included from the French National Health Insurance database (SNDS) which covers >97.5% of French population. Patients were separated in 2 groups according to their date of inclusion: (i) Over 2010-2012 for group 1 and (ii) over 2014-2017 for group 2. Descriptive analyses were performed. Kaplan-Meier method was used to model the duration of treatment induction and maintenance. Fine and Gray tests were used to compare treatment phases durations.

Results

The study involved 4445 prevalent GPA patients (including 1578 incident patients) and 1833 prevalent MPA patients (878 incident patients). Group 1 consisted of 694 and 283 GPA and MPA patients respectively; group 2 included 668 and 463 GPA and MPA patients respectively. Mean age and the sex ratio were stable over time. During the first year after inclusion, the proportion of patients with first-time hospitalized infections, diabetes or renal failure increased between 2010–2012 and 2014–2017. Between the two inclusion periods, the proportions of patients treated with rituximab increased both in the induction and maintenance phases whereas treatment with azathioprine declined (Table 1). As for methotrexate, cyclophosphamide and glucocorticoids, the proportions remained stable.

Conclusion

According to real-life, pharmacoepidemiologic data in GPA and MPA patients, the introduction of rituximab reduced the use of azathioprine without affecting the use of glucocorticoids, although corticosteroids sparing should become a standard of care with the emerging treatment regimens. No reductions in adverse events were observed with the increased use of rituximab.
#1000 Living alone and prognosis in elderly patients with chronic kidney disease: a nationwide study from Denmark
Authors: Thomsen Mette K , Jensen Simon Kok , Heide-Jørgensen Uffe , Slot Matilde , von Heymann Annika , Lauritzen Kira , Johansen Christoffer , Christiansen Christian Fynbo
Published: May 2024

Background and Aims

Patient care is increasingly relying upon involvement of patient relatives, including for patients with chronic kidney disease (CKD). However, patients living alone may be disadvantaged due to a lack of support. We aimed to assess the difference in prognosis after incident CKD in elderly patients between patients living alone versus living with others in a nationwide cohort study.

Method

We identified all patients aged 65 years or older with incident CKD from January 1, 2016, to December 31, 2020, with follow-up until December 31, 2021. We used data from national registries to identify CKD from out-patient creatinine measurements and linked these data to hospital treatment procedures and information from the Civil Person Registration system by the universal and unique personal identification number assigned to all Danish residents at birth or immigration.

We defined incident CKD as having two or more estimated glomerular filtration rate (eGFR) values below 60 ml/min/1.73 m2 registered at least 90 days apart. We categorized eGFR according to “Kidney Disease: Improving Global Outcomes” (KDIGO) CKD stages into 45-59 ml/min/1.73 m2 (mildly/moderately decreased), 30-44 ml/min/1.73 m2 (moderately/severely decreased), 15-29 ml/min/1.73 m2 (severely decreased), <15 ml/min/1.73 m2 (kidney failure).

We assessed cohabitation (living alone, or living with others), also in national registry data. We described the population by age group, sex and stage of CKD. Analyzing mortality, we followed patients from date of CKD to death or end of follow-up, whichever came first. We calculated the median time to death, using age as the time scale and reported these by cohabitation status with 95% confidence intervals (CIs).

In further analyses, we will estimate the cumulated proportion who experienced a rapid decline in kidney function, as a measure of prognosis, and model the association between cohabitation and prognosis/mortality in regression models.

Results

We identified 204 662 elderly patients with CKD from 2016 to 2020, with 55% women and 38% 80 years or older. For severity, 84% had mildly/moderately decreased kidney function, 13% had moderately/severely decreased kidney function, 2% had severely decreased kidney function and only less than 1% (457 patients) presented with kidney failure.

At index, 55% lived with others and 45% lived alone. Overall, 53 715 died during follow-up, and median age at death was 82 (95% CI: 82;82) for CKD patients living together with someone, but 78 (95% CI: 77;78) for those living alone.

Conclusion

The results are preliminary, and further analyses, including age adjustment, mortality estimates and information on adult children, will be available for presentation at the ERA conference 2024.
#1447 Calcimimetics improve impaired cardiac function and contractility in chronic phosphate loading by activating the CaSR/cAMP signaling cascade
Authors: Grund Andrea , Haffner Dieter , Leifheit-Nestler Maren
Published: May 2024

Background and Aims

High phosphate loading stimulate the synthesis of PTH and FGF23 and is associated with increased cardiovascular (CV) mortality. In hemodialysis patients, the administration of calcimimetics led to reductions in PTH and FGF23 and the latter was associated with a lower rate of CV events. We have previously shown that mice with a high dietary phosphate load show elevated PTH and FGF23 levels and develop impaired systolic cardiac function, which could be improved by calcimimetics. Calcimimetics are allosteric activators of the calcium-sensing receptor (CaSR). Phosphate (Pi) was shown to inactivate the parathyroid CaSR at concentrations >1.4 mM Pi. Whether calcimimetics contribute to CV event reduction indirectly via lowering PTH and FGF23 or directly via activation of the cardiac CaSR is unknown.

Method

Wild-type mice were fed a high phosphate diet (HPD) ± etelcalcetide (Etl) or a normal phosphate diet (NPD), cardiac function was assessed by echocardiography and Millar catheterization, and cardiac tissue was harvested for histology and RNAseq analyses. In addition, isolated adult mouse cardiomyocytes (AMCM) were stimulated ex vivo with PTH, FGF23 or Pi, contractility and calcium handling were measured with the addition of Etl and activity analyses were performed.

Results

In addition to the positive effect on HPD-induced systolic cardiac dysfunction, Etl improved impaired LV contractility and reduced fibrosis. RNAseq analyses revealed reduced Ca, PKA and cAMP signaling by HPD. Ex vivo stimulation of AMCM with PTH and FGF23 had no functional effects. In contrast, Pi significantly worsened contractility and Ca handling, which was blunted by Etl co-stimulation. Downstream of cardiac CaSR, Pi reduced the formation of cAMP, which led to PKA-dependent dephosphorylation of PLN and subsequently to lower Serca2a activity, which was ultimately responsible for the reduced contractility. Etl led to improved cardiomyocyte contractility via increased cAMP synthesis and increased PLN phosphorylation and Serca2a activity.

Conclusion

Our data suggest that Etl ameliorates the Pi-induced pathologic cardiac phenotype associated with high phosphate load via direct activation of CaSR/cAMP signaling cascade, resulting in improvement of cardiomyocyte contractility.
#2255 Impact and interest of using the EKFC formula instead of CKD-EPI in estimating GFR in the laboratory on clinical practice
Authors: Derain-Dubourg Laurence , Lemoine Sandrine , Letourneau Pierre , Cabezas Lara , De Mul Aurelie , Chardon Laurence
Published: May 2024

Background and Aims

Early diagnosing Chronic Kidney Disease (CKD) is of major importance in daily practice, and the automatic reporting of the estimated glomerular filtration rate (eGFR) for all plasma creatinine (Pcr) determinations is mandatory. The CKD-EPI 2009 formula [1] is considered the most accurate creatinine-based GFR estimating formula in adults in Europe and is currently utilized by laboratories. However, CKD-EPI equation is inadequate in young adults < 25 years and CKD-EPI equation is debated in the elderly over 75 years, with the BIS1 equation [2] showing better performance in this age group. The creatinine-based European Kidney Function Consortium (EKFC) equation [3] provides continuous GFR estimation from 2 years to adulthood and the elderly, presenting itself as a potential alternative to both the CKD-EPI and BIS1 equations. Our objective was to assess the impact of using the EKFC equation (and/or BIS1 in the elderly) compared to CKD-EPI in daily practice in identifying patients with a GFR < 60 or < 30 ml/min/1.73 m2, which represents the threshold for referring to a nephrologist and adjusting drug dosage, respectively.

Method

We retrieved data from the laboratory database, including gender, age, and the lowest measurement of Pcr for all patients over 18 years who underwent Pcr determination in November 2023. eGFR was calculated for all patients using the CKD-EPI and the EKFC equation. For patients over 70 years, eGFR was also estimated with the BIS1 equation. Pcr was assessed using an enzymatic method traceable to IDMS (Architect c®, Abbott Diagnostics). Results were expressed as the mean bias between EKFC and BIS1, and CKD-EPI (considered as the reference) according to age groups, and as the number of patients misclassified as < 60 or < 30 ml/min/1.73 m2.

Results

10 066 patients (50.5% females, mean age 56.0 ± 21.2 years [18.0-106.7]) underwent Pcr determination (mean 84.7 ± 72.3 µmol/L) with 1 706 (16.9%) and 405 (4.0%) having a GFR < 60 or < 30 ml/min/1.73 m2, respectively.

EKFC and BIS underestimated CKD-EPI eGFR in all groups, but especially in the groups of young adults and the elderly. However, the number of misclassified patients is small, except in the elderly when CKD-EPI is considered less accurate.

Conclusion

The use of EKFC in laboratories to estimate eGFR offers continuous GFR estimation from 2 years to adulthood and elderly and could be an alternative to both CKD-EPI and BIS1. The automatic reporting of eGFR with EKFC by laboratories in Europe could allow for an earlier diagnosis of CKD and initiation of nephroprotection in young adults, in addition to providing better nephrological care for the elderly.
#321 Hemodiafiltration for ESRD patients
Authors: Zhang Fan , Bai Yan , Wang Weiqiong , Zhong Yifei
Published: May 2024

Background and Aims

This systematic review and meta-analysis were designed to determine the effect of hemodiafiltration (HDF), or hemofiltration (HF) compared to hemodialysis on the prognosis of end-stage renal disease (ESRD) patients.

Method

PubMed, Embase, and Web of Science were searched for published studies from reception to 18 September 2023, and updated search on October 15, 2023. Randomized clinical trials (RCTs) or cohort studies evaluated prognosis of hemodiafiltration, or hemofiltration compared to hemodialysis in patients with ESRD were included. Data was synthesized based on heterogeneity with corresponding model selected, and trial sequential analyses were conducted. The primary outcome was all-cause mortality, and secondary outcome was cardiovascular mortality and dialysis adequacy. Outcomes were reported as relative risk (RR), hazard ratio (HR), or mean difference (MD) with a 95% confidence interval (95% CI).

Results

There were 26 RCTs, 10 cohort studies, and total of 36 articles included in the meta-analysis. Pooled results of RCTs showed a statistically significant difference in all-cause mortality between HDF/HF group and standard hemodialysis group (RR = 0.86; 95% CI 0.78-0.96; I2 = 29%; Fig. 1). Trial sequence analysis (TSA) showed that the all-cause mortality curve crossed the traditional and TSA boundaries, but it was not yet as informative as desired. Subgroup analysis found that ESRD patients treated with hemodiafiltration had a 13% lower risk of death (RR = 0.87; 95% CI 0.78-0.97; Fig. 1) with no heterogeneity (I2 = 0%). In contrast, the effect of hemofiltration on mortality risk in ESRD patients was not significant (RR = 0.70; 95% CI 0.39-1.29; Fig. 1). A similarly statistically significant difference in cardiovascular mortality (RR = 0.747; 95% CI 0.607-0.917; I2 = 0%; Fig. 2) for RCTs. In addition, HDF/HF treatment was significantly associated with improved dialysis adequacy (Assessed by Kt/V) in ESRD patients (MD: 0.09; 95% CI 0.01-0.17; I2 = 96%). The combined results of cohort studies showed a 28.6% reduction in mortality risk in ESRD patients treated with HDF (HR = 0.714; 95% CI 0.575-0.886; I2 = 84%; Fig. 3), with an HR for cardiovascular mortality of 0.708 (95% CI 0.604-0.829; I2 = 0%; Fig. 4).

Conclusion

Overall, HDF/HF was associated with reduced all-cause mortality and cardiovascular mortality in patients with ESRD and contributed to improved dialysis adequacy.
#1157 Body mass and fluid balance in dialysis: global profiles in Apollo Dial DB
Authors: Croft Kaitlyn , Wolf Melanie , Jiao Yue , Winter Anke , Nikam Milind , Stuard Stefano , Guinsburg Adrian , Koulechov Kirill , Mcguigan Stuart , Usvyat Len , Larkin John , Maddux Frank
Published: May 2024

Background and Aims

Fluid management is a fundamental component of dialysis care. Achieving euvolemia and avoiding fluid overload can be challenging in dialysis. Apollo Dial DB, an anonymised dialysis database from a global kidney care network, was used to gain deeper insights in patterns of patient body mass and fluid balance during dialysis treatments worldwide.

Method

Apollo Dial DB, a global anonymised dialysis database, contains real-world data from patients in 40 countries beginning January 2018 throughout March 2021. Parameters include demographics, diagnoses, laboratories, medications, treatments, quality of life, and outcomes. This analysis assessed body mass and fluid status parameters on patients in Asia-Pacific (AP), Europe, Middle East, and Africa (EMEA), Latin America (LA), Northern America (NA). In addition, bioimpedance for body compositions of patients was assessed as it was available in AP, EMEA, and LA.

Results

The first version of the Apollo Dial DB includes data on 543, 169 patients, with 4.6% from AP, 13.9% from EMEA, 7.0% from LA, and 74.5% from NA countries. EMEA and NA have a higher proportion of patients in the bigger height categories versus the AP and LA regions (Table 1). There is a difference in mean body weight post dialysis of more than 10 kg between regions; the highest weights were observed in EMEA and NA in contrast to the AP and LA regions. Average albumin levels were consistent in all global regions. Intradialytic weight gain is lowest in EMEA at 1.8 kg and highest in NA at 2.2 kg between treatments. While ultrafiltration volume ranged from 2.0 L to 2.4 L, being the highest in AP and NA. Bioimpedance measures defining body compositions were available for the majority of patients in AP (59.3%), EMEA (86.9%), and LA (90.7%). Patient averages in EMEA are slightly higher for ATM, FTM, LTM, TBW than for LA and AP; this is somewhat explained by the differences in body weight between the cohorts (Fig. 1).

Conclusion

A descriptive analysis of the body mass and fluid status across minor and major regions bring to light key profiles and differences in the characteristics of dialysis patients across the world and fluid management practices in dialysis care. Differences in intradialytic weight gain may deserve further analysis considering the impact of dialysis modality on fluid balance, such as potential influences of convective therapies. These findings act as benchmarks for the nephrology community. Apollo Dial DB offers opportunities for investigators to conduct global analytics and advance kidney disease research.
#2502 The CONVINCE randomized trial found positive effects of hemodiafiltration on quality of life in patients with kidney disease on dialysis
Authors: Rose Matthias , Fischer Felix , Hockham Carinna , Vernooij Robin Wm , Barth Claudia , Canaud Bernard , Cromm Krister , Davenport Andrew , Fischer Kathrin I , Jaha Hanna , Schappert Anna , Blankestijn Peter J
Published: May 2024

Background and Aims

Health-related quality of life of ESKD patients is negatively affected by disease-specific symptoms and can additionally be impaired by renal replacement therapy. Previous studies indicate that hemodiafiltration (HDF) may have a positive impact on the patients’ perceived health status compared to hemodialysis (HD), but overall evidence has been inconclusive. We investigated whether HDF is beneficial with respect to the patients’ perceived health status in the CONVINCE Trial.

Method

The CONVINCE Trial is an international multi-center, prospective, randomized, open label, controlled trial, comparing benefits and safety high-dose HDF versus high-flux HD. All-cause mortality was the primary outcome of the trial and a broad range of Patient-Reported Outcomes (PROs) were investigated as secondary outcomes. Eight generic health domains (Physical Function, Pain Intensity, Pain Interference, Fatigue, Sleep Disturbance, Depression, Anxiety, Ability to Participate in Social Roles and Activities) were assessed using the Patient-Reported Outcome Measurement Information System, PROMIS®-29 v2.0 profile, and an additional PROMIS short-form assessing Cognitive Function. PROs were collected every three months over the course of the study. As the perceived health status is likely related to mortality, we estimated the effect of HDF on PROs using a joint modelling approach to account for potential bias by selective dropout due to death.

Results

A total of n = 1 360 patients have been randomized to HD (n = 677) and HDF (n = 683). Both groups were comparable at baseline, with physical function (44.0 on the PROMIS T-score metric) considerably lower than the general population. Median follow-up was 30 months. We could obtain 84% of the planned PRO follow-up assessments on average. Overall, we found a steady decline in Health-Related Quality of Life (HRQoL) over the observation period; with statistically significant group differences for Physical Function (P  =  .047), Cognitive Function (P  =  .049), Pain Interference (P  =  .027) and the Ability to Participate in Social Roles and Activities (P  =  .023), all favouring HDF over HD.

Conclusion

Within the CONVINCE trial we have applied a comprehensive assessment of PROs comparing HDF with HD. Along with a beneficial effect on survival rates, we observed a slower decline in patients perceived health status when treated with HDF compared to HD. CONVINCE provides further evidence that HDF is beneficial in terms of quality of life.
#1683 Gut permeability, circulating bacterial fragments, and left ventricular strain in peritoneal dialysis
Authors: LI Chuanlei , Szeto Cheuk Chun
Published: May 2024

Background and Aims

There are limited data on the association of gut permeability, circulating bacterial fragment load, left ventricular strain in patients on peritoneal dialysis (PD). We aimed to measure circulating bacterial fragments, NT-proBNP, calprotectin and zonulin levels, and to evaluate their association with gut permeability, circulating bacterial fragment load, left ventricular strain and clinical outcomes on PD patients.

Method

We performed a single-center prospective cohort study. Patients who were planned for peritoneal dialysis were recruited. Serum endotoxin, bacterial DNA, NT-proBNP, calprotectin and zonulin levels were measured. Primary outcomes were technical and patient survival, secondary outcomes were hospitalization data.

Results

One hundred and eight patients were recruited. No correlations between circulating bacterial fragments, NT-proBNP, calprotectin and zonulin levels in PD patients. Circulating bacterial fragments, calprotectin and zonulin levels are positively correlated with insulin resistance index (bacterial DNA: P  =  .002, calprotectin: P  =  .014, zonulin: P  =  .006), while NT-proBNP level is associated with volume overload in PD patients (volume of overhydration: P  =  .000, E:I ratio: P  =  .000), peritoneal characteristics (D/P4: P  =  .004, MTAC: P  =  .048). NT-proBNP level have a negative correlation with nutritional characteristics (albumin: P  =  .000, hemoglobin: P  =  .033) and residual GFR (P  =  .000). In univariate analysis of PD patient survival, NT-proBNP is associated with patient survival (P  =  .003), but this association become insignificant after multivariate analysis of clinical confounding factors. NT-proBNP is the strongest independent predictor of technical survival rate in PD patients (P  =  .005). Patients in the highest tertiles of NT-proBNP and calprotectin have lower technical survival rates, but only patients in the highest tertiles of NT-proBNP, not calprotectin, have lower patient survival. NT-proBNP is also correlated with the number of hospitalizations per year (P  =  .004) and total hospitalization time (P  =  .012) in PD patients. Endotoxin and bacterial DNA levels in PD patients have no predictive value for PD patient survival, technical survival, number of hospitalizations per year, and total hospitalization time.

Conclusion

There is no correlation between gut permeability, circulating bacterial fragments, and impairment of left ventricular function in PD patients. Circulating bacterial fragments levels and gut permeability are associated with insulin resistance, while impairment of left ventricular function is associated with solution overload. Bacterial fragment levels have no predictive value on survival rate, technical survival rate and hospitalizations data in PD patients. NT-proBNP is the strongest independent predictor of technical survival rate in PD patients.
#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

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

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<.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

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

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 < .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

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 < 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

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 < 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 < 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

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 < 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

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

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.