The effects of Banff histological diagnoses on kidney transplant outcome have been well characterized. However, repeated observation of such histological injury across multiple biopsies in kidney transplant recipients remains insufficiently explored. In an observational cohort (N=1819 transplantations with 5736 post-transplant biopsies, recurrent event survival models quantified transitions between diagnoses of T-cell mediated rejection (TCMR), antibody-mediated rejection (AMR), DSA-negative C4d-negative microvascular inflammation (MVI DSA-/C4d- ), BK polyomavirus nephropathy (BKPyVAN), borderline TCMR (bTCMR), and probable AMR (pAMR), revealing patterns in the disease trajectories. In two observational cohorts (N=1818 transplantations with 5732 biopsies, N=853 transplantations with 975 biopsies), time-dependent cumulative covariates were constructed for TCMR, AMR, MVI DSA-/C4d- and BKPyVAN, enabling estimation of associations of repeated diagnoses with graft failure using multivariable cause-specific Cox models. The incidence rate of a diagnosis was most strongly associated with earlier diagnosis of the same type, but associations between different types of diagnoses also occurred. The hazard of kidney graft failure was significantly increased by repeated observation of TCMR in multiple biopsies (HR 7.97, 95% CI 4.94 - 12.86), as well as by repeated AMR (HR 6.19, 95% CI 3.15 - 12.17), repeated MVI DSA-/C4d- (HR 4.53, 95% CI 2.15-9.54) and repeated BKPyVAN (HR 10.90, 95% CI 5.83 – 20.35). The hazard of graft failure was increased more after repeated diagnoses in transplants than after first diagnoses. The effects of repeated TCMR and repeated AMR remained significant even when observed in protocol biopsies in the absence of graft dysfunction. Repeated observation of BKPyVAN was the most detrimental of all diagnoses when observed in indication biopsies, but it was the least harmful when observed in protocol biopsies. Incidence of Banff histological diagnoses appears to be affected by earlier diagnoses, especially those of the same type. These repeated observations of a specific diagnosis have an additional effect on the hazard of graft failure, underscoring a critical unmet need for adequate treatment strategies for these recurrent or persistent injury processes. In two observational cohorts of 1819 and 750 kidney transplant recipients, kidney transplant biopsies were taken at multiple time points after transplantation. Based on the Banff classification for transplant pathology, various post-transplant diseases were diagnosed, often at more than one time point during follow-up. We assessed patterns in the occurrence of diagnoses over time, and related these diagnoses to survival of the kidney grafts using survival models with time-dependent cumulative diagnoses. We found that repeated observation of the same diagnosis was much more common than consecutive observations of different diagnoses. Repeated diagnoses of tissue injury also decreased kidney graft survival more compared to single diagnoses. This indicates that treatment options for patients with repeated or persistent diagnoses are currently inadequate and novel strategies are needed.

Abstract Accurate, reproducible interpretation of kidney allograft biopsies is critical for the diagnosis of graft injury and for informing prognosis and clinical management. The international Banff classification is a consensus diagnostic system based on semiquantitative histological lesion scoring according to either lesion extent or severity in kidney transplant biopsies. However, pathologist scoring is limited by interobserver variability, constrained scalability, and the inherent nature of the scoring system itself. Here we present BanffNET, a weakly supervised, probabilistic deep learning framework that combines self-supervised feature extraction with a novel Bayesian multiple-instance learning framework to predict (continuously) the full spectrum of Banff lesion scores directly from whole-slide images (WSIs). Using lesion-specific aggregation functions tailored to localized (modeling severity) and diffuse histological lesions (modeling extent), BanffNET generates interpretable, patch-level probability maps and calibrated slide-level scores. BanffNET’s performance was assessed relative to consensus, biological correlates of rejection and clinical outcome, demonstrating superior consistency, transportability and generalization. Trained on 7,533 WSIs from three cohorts, BanffNET demonstrates consistent performance on 12,687 WSIs across five external validation cohorts, matching or surpassing individual expert pathologists across lesion assessments. BanffNET scores align more closely than pathologist Banff scores with molecular profiles of rejection, offering an objective, transparent, biologically grounded framework for computational pathology with relevance beyond kidney transplantation.

Chronic kidney disease (CKD) is characterized not only by progressive fibrosis but also by systemic endothelial dysfunction and inflammation. Platelets, traditionally recognized for their role in hemostasis, also serve as key modulators of endothelial activation and immune cell recruitment. Platelet activation is commonly observed in patients with CKD and contributes to the proinflammatory environment. Although platelet-endothelial interactions are well-characterized in cardiovascular disease, their role in renal endothelial dysfunction and inflammation remains poorly understood. To investigate this, we used the unilateral ureteral obstruction (UUO) model in mice, to examine how platelet activation influences endothelial responses and monocyte/macrophage recruitment in the early phase of renal fibrosis development. Platelet depletion reduced the number of infiltrating macrophages in kidney tissue, decreased expression of endothelial activation and inflammation markers, and preserved the peritubular capillary (PTC) integrity. Further in vitro studies using human umbilical vein endothelial cells (HUVECs) showed that activated platelets induced endothelial dysfunction and inflammation, in line with the in vivo findings. To recapitulate the vascular microenvironment, we performed a shear flow-based transmigration assay. Monocyte adhesion and transendothelial migration significantly increased when endothelial cells were pretreated with activated platelets compared to unstimulated controls. Moreover, the presence of platelets on the inflamed endothelium further enhanced monocyte migration, suggesting a synergistic effect in promoting immune cell recruitment. Collectively, our findings highlight that activated platelets contribute to endothelial dysfunction, inflammation, and monocyte infiltration in early kidney injury, suggesting their potential as a therapeutic target to mitigate microvascular injury and preserve renal vascular integrity in kidney disease.

Background Diagnostic interpretation of kidney allograft biopsies using the Banff classification remains variable, but the determinants of this variability are not fully defined. We performed a global, fully digital multi-reader study to identify the principal drivers of disagreement in Banff-based assessment. Methods Thirty six kidney transplant biopsies were independently scored by 67 renal pathologists on a standardized digital platform. Readers assessed Banff lesions on hematoxylin and eosin, periodic acid Schiff, and Jones' silver stains; final diagnostic categories were assigned using prespecified Banff-based decision rules. Interobserver agreement was quantified with Gwet's agreement coefficient (AC) statistics. Determinants of diagnostic agreement were evaluated) using pairwise mixed-effects logistic regression, and reader similarity was examined by principal component analysis (PCA) with post hoc molecular annotation. Results Agreement for final diagnostic categories was moderate (Gwet's AC1, 0.55; 95% CI, 0.47 - 0.63). Lesion-level agreement varied substantially, with lowest agreement for selected threshold-dependent inflammatory or semi-quantitative lesions, including interstitial inflammation in areas of IFTA, peritubular capillaritis and arteriolar hyalinosis. Diagnostic concordance differed markedly across biopsies, indicating strong case-level heterogeneity. In pairwise models, differences in active inflammatory and vascular lesion scoring were the strongest correlates of diagnostic disagreement; reader experience and geography contributed minimally. Principal component analysis showed reader variation was organized along two dominant axes: a rejection-calling threshold axis linked mainly to tubulointerstitial inflammatory injury, and a T cell-mediated (TCMR/TI) and antibody-mediated/microvascular (AMR/MVI) inflammation-oriented phenotypic classification axis. Conclusion Interobserver variation in Banff-based kidney transplant biopsy assessment is structured rather than random and driven mainly by how readers threshold and integrate key inflammatory lesion compartments rather than experience or geographic location.

Background. Kidney preservation techniques, such as hypothermic machine perfusion (HMP), improve graft outcomes in deceased-donor kidney transplantation by pausing graft metabolism and ameliorated ischemia–reperfusion injury (IRI) but do not completely eliminate injury. Alkaline phosphatase (ALP) has been postulated to reduce IRI-induced kidney injury through the conversion of extracellular adenosine triphosphate into adenosine. This study aimed to evaluate whether ALP offers protection during deceased-donor kidney storage. Methods. Sixteen abattoir porcine kidneys (8 ALP and 8 with placebo) were procured after euthanization and exposed to 30 min of warm ischemia followed by 24 h of HMP or static cold storage (SCS). Reperfusion was partly simulated by 240 min of normothermic machine perfusion (NMP). Throughout NMP, we obtained functional, biochemical, and histological parameters. Results. Significantly lower urine production accompanied by lower perfusate pCO2 and higher pH were observed in the ALP group throughout NMP. At the end of NMP, intracellular ATP reserves and oxygen consumption were significantly higher in the ALP-treated group. Metabolomics analysis with principal component analysis demonstrated significant differences between the ALP and placebo groups in glycolysis and mitochondrial metabolites, along with a significantly attenuated rise in perfusate lactate dehydrogenase levels. Conclusions. ALP supplementation during HMP was associated with lower urine production and energetic stress, with a shift toward less metabolic dysfunction and graft injury by the end of NMP. Our findings suggest an improvement in the early metabolic incompetency that characterizes delayed graft function in humans. Further research should elucidate whether these findings result in enhancement of graft functionality after transplantation.

Exposure to fine particulate matter (PM2.5) has been associated with an increased risk of chronic kidney disease (CKD), and exposure to PM2.5 is known to aggravate ischemia/reperfusion injury-induced acute kidney injury (AKI) in mice. The impact of PM2.5 concentration on the incidence of CKD, AKI, and glomerulopathy in the megacity of Sao Paulo is has never been described. We analyzed meteorological variables, PM2.5 concentrations, and hospital admissions in São Paulo, Brazil, from 2011 to 2021. Admissions were categorized by age and sex. We analyzed 37,170 records, 55% representing males. Exposure to PM2.5 was found to increase CKD hospitalization risk by 1-4 times (95% CI: 1.009-1.18), across different age groups and exposure levels. Long-term exposure to a high PM2.5 concentration (65 μg/m3) increases that risk considerably for individuals aged 19-50 years (relative risk [RR]: 1.01; 95% CI: 1.005-1.015 and RR: 1.013; 95% CI: 1.01-1.018, respectively), the risk being ≤ 2.5 times higher in men aged 51-75 years (RR: 1.025; 95% CI: 1.015-1.032). The AKI hospitalization risk after prolonged exposure to high PM2.5 concentrations was highest for men aged 19-50 years (RR: 1.04; 95% CI: 1.012-1.07). The risk of glomerulopathy was highest in the < 40-year age group, especially among men exposed to concentrations of 15 μg/m3 (RR: 1.02; 95% CI: 1.007-1.025) and 65 μg/m3 (RR: 1.07; 95% CI: 1.02-1.11). Such exposure also increased the cumulative risk of hospitalization for membranous nephropathy, regardless of sex and age. Our findings underscore the urgent need to develop global strategies for air pollution reduction.

KEY POINTS:Stable kidney transplant recipients with early stage 1 lymphoid aggregates displayed gene signatures indicative of a tolerogenic immune environment. Participants with early stage 1 lymphoid aggregates demonstrated a trend toward better kidney function trajectories and lower risk of graft failure. Early stage 1 lymphoid aggregates may represent beneficial immune surveillance mechanisms promoting long-term graft stability in low-risk transplant recipients. BACKGROUND:The presence of lymphoid tissues and their effect on long-term kidney graft outcome remains unclear. This study investigates the occurrence, molecular and phenotypic characteristics of lymphoid aggregates (LA) in protocol biopsies of clinically stable kidney transplant recipients, and their correlation with long-term clinical outcome. METHODS:We retrospectively analyzed 414 protocol biopsies from a multicenter cohort of 278 stable kidney transplant recipients taken at 6, 12, or 24 months post-transplant. On a subset of 16 biopsies at 6 months post-transplant, mRNA gene expression analysis was performed using Nanostring Banff Human Organ Transplant panel alongside phenotypic analysis with immunostaining for developmental staging of LA. Finally, the presence of LA was correlated to various clinical kidney allograft outcomes. RESULTS:Stage 1 LA were characterized by upregulation of genes linked to immune regulation ( LAG3, CTLA4, FOXP3 ), T -cell signaling, and chemotaxis pathways, with enrichment of regulatory T cells, memory T cells, T follicular helper cells, and dendritic cells. Immunohistochemistry confirmed higher numbers of FOXP3+ regulatory T cells and dendritic cells in stage 1 LA, while high endothelial venules were absent. Over follow-up, participants with stage 1 LA showed slightly higher eGFR values and a trend toward better graft survival compared with those without LA or with stage 2 LA, although most differences did not reach statistical significance. CONCLUSIONS:In stable kidney transplant recipients, stage 1 LA displayed molecular and phenotypic features consistent with a regulated immune environment. The molecular and immunohistochemical analysis of stage 1 LA suggests a more regulatory molecular phenotype and composition, which may contribute to better long-term graft survival observed in this cohort of functionally stable transplant recipients. Observed trends toward more favorable outcomes suggest that early LA may not be deleterious and could represent local immune regulation, although larger prospective studies are needed to confirm these findings.

Accurate pathological assessment of tissue samples is key to diagnosis and optimal treatment decisions. Traditional pathology techniques suffer from subjectivity, resulting in interobserver variability and limitations in identifying subtle molecular changes. Omics approaches provide both molecular evidence and unbiased classification, which increases the quality and reliability of final tissue assessment. Here, we focus on mass spectrometry (MS)-based proteomics as a method to reveal biopsy tissue differences. For MS data to be useful, molecular information collected from formalin-fixed paraffin-embedded-biopsy tissues needs to be consistent and quantitatively accurate and contain sufficient clinically relevant molecular information. Therefore, we developed an MS-based workflow and assessed the analytical repeatability on 36 kidney biopsies, ultimately analyzing molecular differences and similarities of over 5000 proteins per biopsy. An additional 301 transplant biopsies were analyzed to understand other physical parameters, including the effects of tissue size, standing time in the autosampler, and the effect on clinical validation. MS data were acquired using data-independent acquisition, which provides gigabytes of data per sample in the form of high proteome representation, at exquisitely high quantitative accuracy. The formalin-fixed paraffin-embedded-based method optimized here provides a coefficient of variation <20%, analyzing >5000 proteins per sample in parallel. We also observed that tissue thickness does affect the outcome of the data quality: 5 μm sections show more variation in the same sample than 10 μm sections. Notably, our data reveal an excellent agreement for the relative abundance of known protein biomarkers with kidney transplantation lesion scores used in clinical pathological diagnostics. The findings presented here demonstrate the ease, speed, and robustness of the MS-based method, where a wealth of molecular data from minute tissue sections can be used to assist and expand pathology, and possibly reduce the interobserver variability.

BACKGROUND:Plasma cell-rich rejection (PCRR) is an ill-defined type of renal allograft rejection currently considered a subtype of T cell-mediated rejection. Our study analyzed the clinical course, Banff lesion scores, and mRNA expression of PCRR compared with archetypical types of (late) rejection to better understand and define this presentation in kidney transplants. METHODS:We retrospectively scored the last known biopsy in 263 renal transplant recipients, including 42 PCRR cases. Banff lesion scores and clinical outcomes were assessed. Bulk RNA sequencing with CIBERSORTx deconvolution and gene set variation analysis profiled immune-cell composition and pathway activity in an additional set of 140 renal transplant biopsies. Dimensionality reduction (principal component analysis, uniform manifold approximation and projection, and diffusion maps) and unsupervised clustering evaluated the relationship between PCRR and other rejection types. RESULTS:PCRR was associated with higher Banff chronic lesion scores and chronicity index but not activity scores. Graft survival and renal function were comparable with other forms of late rejection. Plasma-cell abundance correlated positively with CD8 T cells but negatively with B cells and plasmacytoid dendritic cells. PCRR biopsies showed enrichment for endothelial injury and fibrosis-related pathways and mast-cell/B-cell activation modules. The overall pathway signature of PCRR most closely resembled chronic-active T cell-mediated rejection. Principal component analysis, uniform manifold approximation and projection, and diffusion analysis revealed no distinct transcriptional cluster separating PCRR from other (late) rejection types. CONCLUSIONS:PCRR exhibits chronic tissue injury, innate/humoral pathway activation, and shares the greatest molecular similarity with chronic-active T cell-mediated rejection, supporting its placement within the continuum of late kidney allograft rejection.

Accurate pathological assessment of tissue samples is key to diagnosis and optimal treatment decisions. Traditional pathology techniques suffer from subjectivity, resulting in interobserver variability and limitations in identifying subtle molecular changes. Omics approaches provide both molecular evidence and unbiased classification, which increases the quality and reliability of final tissue assessment. Here, we focus on mass spectrometry (MS)-based proteomics as a method to reveal biopsy tissue differences. For MS data to be useful, molecular information collected from formalin-fixed paraffin-embedded-biopsy tissues needs to be consistent and quantitatively accurate and contain sufficient clinically relevant molecular information. Therefore, we developed an MS-based workflow and assessed the analytical repeatability on 36 kidney biopsies, ultimately analyzing molecular differences and similarities of over 5000 proteins per biopsy. An additional 301 transplant biopsies were analyzed to understand other physical parameters, including the effects of tissue size, standing time in the autosampler, and the effect on clinical validation. MS data were acquired using data-independent acquisition, which provides gigabytes of data per sample in the form of high proteome representation, at exquisitely high quantitative accuracy. The formalin-fixed paraffin-embedded-based method optimized here provides a coefficient of variation <20%, analyzing >5000 proteins per sample in parallel. We also observed that tissue thickness does affect the outcome of the data quality: 5 mu m sections show more variation in the same sample than 10 mu m sections. Notably, our data reveal an excellent agreement for the relative abundance of known protein biomarkers with kidney transplantation lesion scores used in clinical pathological diagnostics. The findings presented here demonstrate the ease, speed, and robustness of the MS-based method, where a wealth of molecular data from minute tissue sections can be used to assist and expand pathology, and possibly reduce the interobserver variability.

Multiclass segmentation of microanatomy in kidney biopsies is an important and non-trivial task in computational renal pathology. In a multicenter study, we densely annotated basic anatomical objects (glomeruli, tubules, and vessels) in 261 regions of interest of 147 kidney biopsy WSIs sourced from the archives of hospitals in Amsterdam, Utrecht, and Leiden (Netherlands). And we trained multiple UNet- and Mask2Former-based models on WSI-level and patch-level splitting methods, and compared their performance across training strategies. Test performance was assessed on 24 annotated renal WSIs from Leuven (Belgium) with sensitivity analysis on the extent of fibrosis and inflammation. At the patch-level, UNet-ResNet18 achieved comparable performances to M2F-Swin-B with average Intersection over Union of all classes (A-IoU, 0.84 vs 0.94), as well as per-class IoU. However, at the WSI-level, M2F-Swin-B significantly surpassed UNet-ResNet18 with large margins on A-IoU (0.84 vs 0.48), with similar observed in per-class IoU. Notably, M2F-Swin-B outperformed UNet-ResNet18 in scenarios characterized by a higher degree of fibrosis and inflammation (A-IoU, 0.76 vs 0.66). Furthermore, at the WSI-level, M2F-Swin-B achieved IoU score of arteries to 0.58, whereas UNet-ResNet18 only achieved 0.33. In this study, we found that the attention mechanism in Mask2Former enables visibly crisper and more uniform segmentation, particularly when data is inadequate. Mask2Former-based models outperform UNet-based models in challenging areas from inflamed and fibrotic renal biopsies.

Management of chronic kidney disease (CKD) remains a major challenge due limited therapeutic options to reverse fibrosis, which is a critical feature in CKD. Partial epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells (TECs) is a key driver of fibrosis, and has become an important focus for kidney protection strategies. Blood platelets, a major source of circulating transforming growth factor beta (TGF-β), are implicated in pathogenesis of CKD, but their involvement in EMT and kidney fibrosis remains uncertain. We used two mouse models of renal fibrosis—diabetic kidney disease (DKD) and unilateral ureter obstruction (UUO)—to examine the connection between platelets, partial EMT, and fibrosis. Platelet inhibition or depletion was performed to assess EMT, cell cycle arrest, and fibrosis. In vitro, platelets were applied to TECs and kidney organoids. To determine the role of TGF-β signaling, we used TGF-βRI inhibitor. Expression of EMT, and fibrosis markers, as well as TGF-β1 signaling, were analyzed using western blot, reverse transcription quantitative PCR (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and immunostaining. In both animal models, platelet inhibition or depletion resulted in reduced expression of cell cycle arrest marker p21, partial EMT and fibrosis. In vitro, activated platelets stimulated cell cycle arrest, EMT, and fibrosis in TECs and kidney organoids. Chronically injured TECs experience cell-cycle arrest which promote a paracrine EMT program in TECs, jointly leading to fibrosis. This platelet-mediated effect on cell cycle arrest and EMT was driven by TGF-β1 signaling, as selective inhibition of the TGF-β receptor rescued these dysfunctional phenotypes. Our study demonstrates that platelets activate the TGF-β1 pathway, leading to cell cycle arrest, EMT and renal fibrosis. These findings suggest that antiplatelet therapies may have potential renoprotective effects by protecting tubular homeostasis, attenuating partial EMT and fibrosis.

Current applications of deep learning in renal pathology focused on anatomical structures with morphology, yet little research has focused on the performance of models, such as versatility, in regions with severe kidney damage. In this study, we explored the difference in modal/domain shift capabilities between CNN-based and Transformer-based models. Firstly, we adopted two splitting strategies—WSI-level and patch-level—to stimulate sampling on multiple modal data distribution (i.e., renal WSIs collected from multi-centers). Then, we trained multiple CNN- and Transformer-based models on each splitting scheme respectively. We compared cross-splitting performance and analyzed the effective factors of results. For further validation, all models were tested on an independent external dataset for sensitivity analysis on the degree of fibrosis and inflammation. In conclusion, at both the patch- and WSI-level, M2F-Swin-B substantially outperformed UNet-ResNet18 with an average Intersection over Union (A-IoU) and per-class IoU. Notably, M2F-Swin-B outperformed UNet-ResNet18 in areas of a higher degree of fibrosis and inflammation and, a higher IoU score of arteries. In this study, we developed a robust multi-class segmentation pipeline for kidney histology. Moreover, we showed that the attention mechanism in Mask2Former enables visibly crisper and more uniform segmentation, particularly when the data is inadequate.

Community-acquired pneumonia (CAP) is a leading cause of death, with mortality linked to an unbalanced host response. Sirtuin (Sirt)1, a histone deacetylase, regulating metabolism and epigenetics, may be fundamental in activating the innate immune response. Sirt1 mRNA expression was significantly reduced in monocytes from CAP patients (n = 76) upon admission compared to healthy controls (n = 42), with levels returning to normal after 30 days. Pharmacological activation of Sirt1 with SRT1720 decreased LPS- and K. pneumoniae-induced IL-6 release in primary human monocytes and decreased NF-κB activation in THP1 cells. In a mouse K. pneumoniae pneumosepsis model, SRT1720 strongly reduced neutrophil influx and degranulation markers in bronchoalveolar lavage fluid, lowered pulmonary concentrations of IL-6 and TNF-α, and reduced lung pathology scores. Simultaneously, it reduced neutrophil content in liver tissue and plasma transaminase levels, alongside a trend toward reduced liver necrosis. Plasma IL-6 and TNF-α were significantly lower in SRT1720-treated mice at 42 h. Finally, while SRT1720 did not impact bacterial loads in the lungs, it reduced bacterial burden in blood, with a similar trend observed in liver homogenates. In conclusion, the Sirt1 activator SRT1720 exerts anti-inflammatory effects on human monocytes, reduces local and systemic inflammation and organ injury, and diminishes bacterial dissemination in murine pneumosepsis.

Levamisole (LMS) is a small imidazole derivative with immunomodulatory properties. Despite its longstanding clinical use in Idiopathic Nephrotic Syndrome (INS), the mechanisms underlying its immune-regulating effects remain poorly defined. In this study, we investigated the in vitro effects of LMS treatment on human B-cells, and in patients included from the LEARNS (LEvamisole as Adjuvant therapy to Reduce relapses of Nephrotic Syndrome) clinical trial. In vitro experiments showed that LMS directly suppresses activation and proliferation in both T-cell dependent and T-cell independent stimulated B-cells, without inducing cytotoxicity. In agreement, transcriptomic profiling demonstrated downregulation of cell cycle-associated genes and genes involved in immunoglobulin synthesis, while genes involved in terminal B-cell differentiation were upregulated, including SLAMF7. Consistently, LMS treatment decreased immunoglobulin expression and secretion while simultaneously inducing the expression of factors associated with a more terminal B-cell phenotype (CD138/CD319). Flow cytometry analysis of blood samples from LMS-treated INS patients revealed reduced circulating B-cell counts. Collectively, these data suggest that LMS acts as a potent modulator of B-cell function that inhibits proliferation and immunoglobulin synthesis, providing mechanistic support for its therapeutic efficacy in INS management. ### Competing Interest Statement The authors have declared no competing interest. Nierstichting, CP 16.03 Zeldzame ziekten fonds Nederland

The Banff classification for kidney transplant pathology dichotomizes the rejection continuum into distinct diagnostic categories, introducing artificial cutoff points and threshold effects. To better reflect the underlying disease spectrum, in this cohort study of 19,500 biopsies from 8873 patients across 10 centers worldwide, we developed two indices for quantifying antibody-mediated rejection/microvascular inflammation and T-cell-mediated rejection/tubulointerstitial inflammation from histological lesion scores and calculated indices for overall activity and chronicity. These indices demonstrate excellent discrimination for the main diagnostic categories of rejection (AUCs from 0.95 to 0.99), with consistent performance across derivation and validation datasets. These indices strictly confine intermediate phenotypes to low index values and are associated to graft failure even within the diagnostic categories, thus reflecting the underlying rejection continuum. In this work, we demonstrate that four continuous indices provide implementable and interpretable global evaluation of kidney transplant histology that align with the continuous nature of the rejection process regardless of the underlying disease cause.

Air pollution is a significant but often overlooked factor in the development of chronic kidney disease. It can start affecting kidney health already during pregnancy. Exposure to air pollution during early life can hinder organ growth, leading to premature birth, low birth weight, hypertension and decreased renal function later in life. Combustion-derived particles, such as soot, are one of the most hazardous components of air pollution. Soot contains unregulated Ultrafine particles (UFPs: <100nm), which exert higher toxicity than larger particles, have significant renal clearance and represent a growing concern for public health.

ABSTRACT Chronic kidney disease (CKD) has emerged as a significant global public health concern. Recent epidemiological studies have highlighted the link between exposure to fine particulate matter (PM2.5) and declined renal function. PM2.5 exerts its harmful effects on various organs through oxidative stress and inflammation. Acute kidney injury (AKI) resulting from ischemia reperfusion injury (IRI) involves similar biological processes involved in PM2.5 toxicity and is a known risk factor for CKD. The objective of this study was to investigate the impact of PM2.5 exposure on IRI-induced AKI. Mice were exposed to PM2.5 or filtered air for 12 weeks before IRI, and were euthanized 48h after IRI. Animals exposed to PM2.5 and IRI exhibited reduced glomerular filtration and impaired urine concentration ability. Moreover, they showed elevated tubular damage markers NGAL and KIM-1, along with significant tubular necrosis. PM2.5 exposure exacerbated local innate immune activation, leading to an increased infiltration of Ly6G+ granulocytes and F480+ macrophages in the kidney. This, in turn, contributed to heightened renal senescence markers and myofibroblast infiltration. Collectively, our findings suggest that AKI-induced hampered tubular function is worsened by PM2.5, leading to reduced resilience to stress, activation of aging mechanisms and early hallmarks of fibrosis. Decreasing PM2.5 and implementing preventive strategies can improve AKI patients outcome and prevent AKI progression.

The N-PATH (Nephrology Partnership for Advancing Technology in Healthcare) program concluded with the 60th European Renal Association 2023 Congress in Milan, Italy. This collaborative initiative aimed to provide advanced training in interventional nephrology to young European nephrologists. Funded by Erasmus+ Knowledge Alliance, N-PATH addressed the global burden of chronic kidney disease (CKD) and the shortage of nephrologists. CKD affects >850 million people worldwide, yet nephrology struggles to attract medical talent, leading to unfilled positions in residency programs. To address this, N-PATH focused on enhancing nephrology education through four specialized modules: renal expert in renal pathology (ReMAP), renal expert in vascular access (ReVAC), renal expert in medical ultrasound (ReMUS) and renal expert in peritoneal dialysis (RePED). ReMAP emphasized the importance of kidney biopsy in nephrology diagnosis and treatment, providing theoretical knowledge and hands-on training. ReVAC centred on vascular access in haemodialysis, teaching trainees about different access types, placement techniques and managing complications. ReMUS recognized the significance of ultrasound in nephrology, promoting interdisciplinary collaboration and preparing nephrologists for comprehensive patient care. RePED addressed chronic peritoneal dialysis, offering comprehensive training in patient selection, prescription, monitoring, complications and surgical techniques for catheter insertion. Overall, N-PATH's strategy involved collaborative networks, hands-on training, mentorship, an interdisciplinary approach and the integration of emerging technologies. By bridging the gap between theoretical knowledge and practical skills, N-PATH aimed to revitalize interest in nephrology and prepare proficient nephrologists to tackle the challenges of kidney diseases. In conclusion, the N-PATH program aimed to address the shortage of nephrologists and improve the quality of nephrology care in Europe. By providing specialized training, fostering collaboration and promoting patient-centred care, N-PATH aimed to inspire future nephrology professionals to meet the growing healthcare demands related to kidney diseases and elevate the specialty's status within the medical community.

Background. Evidence on the optimal maintenance of immunosuppressive regimen in kidney transplantation recipients is limited. Methods. The Amsterdam, LEiden, GROningen trial is a randomized, multicenter, investigator-driven, noninferiority, open-label trial in de novo kidney transplant recipients, in which 2 immunosuppression minimization strategies were compared with standard immunosuppression with basiliximab, corticosteroids, tacrolimus, and mycophenolic acid. In the minimization groups, either steroids were withdrawn from day 3, or tacrolimus exposure was reduced from 6 mo after transplantation. The primary endpoint was kidney transplant function at 24 mo. Results. A total of 295 participants were included in the intention-to-treat analysis. Noninferiority was shown for the primary endpoint; estimated glomerular filtration rate at 24 mo was 45.3 mL/min/1.73 m 2 in the early steroid withdrawal group, 49.0 mL/min/1.73 m 2 in the standard immunosuppression group, and 44.7 mL/min/1.73 m 2 in the tacrolimus minimization group. Participants in the early steroid withdrawal group were significantly more often treated for rejection ( P = 0.04). However, in this group, the number of participants with diabetes mellitus during follow-up and total cholesterol at 24 mo were significantly lower. Conclusions. Tacrolimus minimization can be considered in kidney transplant recipients who do not have an increased immunological risk. Before withdrawing steroids the risk of rejection should be weighed against the potential metabolic advantages.