Nephrology Research Articles

Exploring neurofilament light chain as a biomarker for kidney disease: insights, implications, and future directions

BackgroundNeurofilament light chain (NfL) has emerged as a sensitive biomarker for neuronal injury across various neurological disorders. Recent studies suggest that its elevated serum levels are also associated with kidney disease, including chronic kidney disease, acute kidney injury, and diabetic nephropathy.Main bodyThis paper explores the potential of NfL as a diagnostic and prognostic tool in renal medicine, evaluates its clinical implications, and outlines future research directions. We reviewed recent literature on NfL dynamics, the neuro-renal axis, and the role of the neurofilament light chain in kidney disease across PubMed, Embase, Web of Science, Google Scholar, Cochrane Library, and Scopus. We then analyzed the current evidence on the diagnostic and prognostic value of serum NfL levels in various renal conditions and discussed potential therapeutic implications. Elevated serum NfL levels are associated with several kidney diseases, including chronic kidney disease, acute kidney disease, and diabetic nephropathy. Its increased serum level is related to impaired renal clearance, hormonal changes, and inflammatory processes. NfL levels correlate with traditional renal biomarkers, such as serum creatinine and estimated glomerular filtration rate, and offer additional insights into disease progression and patient prognosis.ConclusionNfL holds promise as a novel biomarker for kidney disease, offering potential advantages for early detection, risk stratification, and monitoring disease progression. Future studies should focus on longitudinal and mechanistic studies to elucidate the pathways linking NfL and kidney function, and clinical trials should be conducted to evaluate the effectiveness of NfL-targeted interventions.

Extra-anatomic aorto-right subclavian bypass after complicated insertion of permanent dialysis catheter

Central venous dialysis catheters are the first line of choice to start on hemodialysis. They could be a bridge to establish another dialysis access. Dialysis catheters are essential of two types: temporary (non-tunnelled) and permanent (tunnelled). Insertion of a dialysis catheter is a ubiquitous procedure in renal medicine. One of the rare but serious complications is vascular erosion. We report on a case of a 68-year-old female patient with acute kidney injury who needed emergency hemodialysis. A permanent dialysis catheter was inserted into her right subclavian vein. There was not good flow in the dialysis catheter’s afferent and efferent lumens. The nephrologist performed a contrast chest roentgenoscopy, which showed that the dialysis catheter followed an abnormal course by passing into the ascending aorta. Emergency surgical extraction of the dialysis catheter was initiated using median sternotomy and supraclavicular incision to identify the entry point of the catheter into the subclavian artery. Due to the dissection of the subclavian artery, we performed an extra-anatomic aorto-subclavian bypass with a saphenous vein graft. The dialysis catheter was inserted through open access into the right subclavian vein.

Strategizing Cardiovascular Management in Diabetic Patients: Insights and Advancements from the 2023 ESC Guidelines for the Management of Cardiovascular Disease in Patients with Diabetes

Communication Strategizing Cardiovascular Management in Diabetic Patients: Insights and Advancements from the 2023 ESC Guidelines for the Management of Cardiovascular Disease in Patients with Diabetes Hongyuan Zhang 1, Darren Green 2 and Yanrong Liu 1,3,* 1 Michael Smith Building, Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M20 4BX, UK 2 Vascular Research Group, Department of Renal Medicine, Salford Royal NHS Foundation Trust, Stott Lane, Salford M6 8HD, UK. 3 The Department of Cardiology, the 1st Affiliated Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China * Correspondence: yanrong.liu@manchester.ac.uk Received: 12 October 2023; Revised: 26 November 2023; Accepted: 27 November 2023; Published: 13 February 2025 Abstract: Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). The 2023 European Society of Cardiology (ESC) guidelines represent a significant advancement in the management of CVD in T2DM, building on the 2019 recommendations. Unlike previous iterations, the updated guidelines focus exclusively on T2DM, excluding pre-diabetes due to limited evidence directly linking it to cardiovascular risk. A notable addition is the SCORE2-Diabetes algorithm, which integrates diabetes-specific factors with traditional risk determinants to estimate the 10-year cardiovascular risk. This personalized risk stratification tool underscores the importance of early identification and management of key contributors, such as hyperglycemia and insulin resistance. The guidelines advocate for a multidisciplinary approach, emphasizing collaboration among diabetes, cardiovascular, and chronic kidney disease specialists to address the complex interplay of these conditions effectively. Moreover, the 2023 ESC guidelines highlight the necessity of individualized treatment strategies to reduce cardiovascular complications in T2DM. By reflecting the heterogeneity of diabetic populations and the evolving pharmacological landscape, these recommendations aim to optimize cardiovascular outcomes. This comprehensive update marks a critical step toward reducing the burden of CVD and improving the quality of life for patients with diabetes.

Ferroptosis in kidney disease: a bibliometric analysis from 2012 to 2024.

Ferroptosis, a novel concept of programmed cell death proposed in 2012, in kidney disease, has garnered significant attention based on evidence of abnormal iron deposition and lipid peroxidation damage in the kidney. Our study aim to examine the trends and future research directions in the field of ferroptosis in kidney disease, so as to further explore the target or treatment strategy for clinical treatment of kidney disease. A thorough survey using the Web of Science Core Collection, focusing on literature published between 2012 and 2024 examining the interaction between kidney disease and ferroptosis was conducted. VOSviewer, CiteSpace, and Biblioshiny were used for in-depth scientometric and visualized analyses. From 2012 to 2024, a total of 2,244 articles met the inclusion criteria for final analysis. The number of annual publications in this area of study showed a steady pattern at the beginning of the decade. The top 3 journals with the highest publication output were Renal Failure, Oxidative Medicine And Cellular Longevity, and Biomedicine & Pharmacotherapy. China and the United States had the highest number of publications. Central South University and Guangzhou Medical University as the most active and influential institutions. Documents and citation analysis suggested that Andreas Linkermann, Jolanta Malyszko, and Alberto Ortiz are active researchers, and the research by Scott J. Dixon and Jose Pedro Friedmann Angeli, as the most cited article, are more important drivers in the development of the field. Keywords associated with glutathione, lipid peroxidation, and nitric oxide had high frequency in the early studies. In recent years, however, there has been a shift towards biomarkers, inflammation and necrosis, which indicate current and future research directions in this area. The global landscape of the ferroptosis research in kidney disease from 2012 to 2024 was presented. Basic research and mechanism exploration for renal fibrosis and chronic kidney disease may be a hot spot in the future.

Update in Nephrology

Background: This timely update in nephrology is based on the proceedings of The American Society of Nephrology (ASN) Kidney Week that was held in San Diego, California between October 23, and October 27, 2024. The meeting had 4 sessions dedicated to high-impact clinical trials and late-breaking science. Methods: This update will present 12 studies including 10 clinical trials. Each trial was published in a major peer reviewed journal on the day of the presentation. This will provide the reader with the opportunity to refer to the published study in its entirety. IgA nephropathy (IgAN) management was a major theme in the meeting, and 5 clinical Trials on that topic are included. Other topics included in this review cover kidney transplantation, sodium-glucose cotransporter 2 (SGLT2) inhibitors in chronic kidney disease (CKD), acute kidney injury (AKI), the role of APOL1 risk variants, semaglutide in non-diabetic CKD patients, potassium binders in hemodialysis patients, and blood pressure management strategies in non-cardiac surgery patients. Results: For each study a brief background will be provided, followed by the results of each individual study, then a conclusion and a statement about the study limitations. Conclusions: This update is a window into recent progress in renal medicine. Advances in basic science are propelling novel medications in the field of nephrology with the potential of impacting direct patient care. The excitement in the renal community is palpable.

Predictive Value of Kidney Failure Risk Equation and Neutrophil Gelatinase-Associated Lipocalin for Chronic Kidney Disease Progression in Chinese Population - A Retrospective Study.

To analyze the independent associations of the Kidney Failure Risk Equation (KFRE) and neutrophil gelatinase-associated lipocalin (NGAL) with end-stage renal disease (ESRD) among patients with chronic kidney disease (CKD) stages 3-5 in China and evaluate their predictive values for ESRD. A total of 716 patients with CKD stages 3-5 at the time of the initial renal medicine referral were retrospectively enrolled, and the study outcome was the observed incidence of ESRD at 2 years after the initial referral. Baseline characteristics were collected, and relevant laboratory indexes, including neutrophil gelatinase-associated lipocalin (NGAL), were detected. The binary logistic regression model was used to analyze the independent associations, and the receiver operating characteristic (ROC) curve was used to assess the predictive values. The 2-year incidence of ESRD was 20.5% (147/716). The 4-variable KFRE, 8-variable KFRE and NGAL were independently associated with ESRD after adjusting for potential confounding factors. The AUCs of the 4-variable KFRE, 8-variable KFRE and NGAL for predicting ESRD among patients with CKD stages 3-5 were 0.711 [standard error (SE): 0.026, 95% confidence interval (CI): 0.662-0.761], 0.725 (SE: 0.025, 95% CI: 0.677-0.774) and 0.736 (SE: 0.024, 95% CI: 0.686-0.785), respectively. The AUC of the 4-variable KFRE plus NGAL was significantly higher than those of the 4-variable KFRE and NGAL alone (0.900 vs 0.711, Z = 6.297, P < 0.001; 0.900 vs 0.736, Z = 5.795, P < 0.001), and the AUC of the 8-variable KFRE plus NGAL was also significantly higher than those of the 8-variable KFRE and NGAL alone (0.911 vs 0.725, Z = 6.491, P < 0.001; 0.911 vs 0.736, Z = 6.298, P < 0.001). The KFRE was able to independently predict progression of CKD stage 3-5 to ESRD in Chinese population. The addition of NGAL to the KFRE was able to elevate the predictive value when applied in predicting 2-year ESRD.

Research hotspots and frontiers of machine learning in renal medicine: a bibliometric and visual analysis from 2013 to 2024.

The kidney, an essential organ of the human body, can suffer pathological damage that can potentially have serious adverse consequences on the human body and even affect life. Furthermore, the majority of kidney-induced illnesses are frequently not readily identifiable in their early stages. Once they have progressed to a more advanced stage, they impact the individual's quality of life and burden the family and broader society. In recent years, to solve this challenge well, the application of machine learning techniques in renal medicine has received much attention from researchers, and many results have been achieved in disease diagnosis and prediction. Nevertheless, studies that have conducted a comprehensive bibliometric analysis of the field have yet to be identified. This study employs bibliometric and visualization analyses to assess the progress of the application of machine learning in the renal field and to explore research trends and hotspots in the field. A search was conducted using the Web of Science Core Collection database, which yielded articles and review articles published from the database's inception to May 12, 2024. The data extracted from these articles and review articles were then analyzed. A bibliometric and visualization analysis was conducted using the VOSviewer, CiteSpace, and Bibliometric (R-Tool of R-Studio) software. 2,358 papers were retrieved and analyzed for this topic. From 2013 to 2024, the number of publications and the frequency of citations in the relevant research areas have exhibited a consistent and notable increase annually. The data set comprises 3734 institutions in 91 countries and territories, with 799 journals publishing the results. The total number of authors contributing to the data set is 14,396. China and the United States have the highest number of published papers, with 721 and 525 papers, respectively. Harvard University and the University of California System exert the most significant influence at the institutional level. Regarding authors, Cheungpasitporn, Wisit, and Thongprayoon Charat of the Mayo Clinic organization were the most prolific researchers, with 23 publications each. It is noteworthy that researcher Breiman I had the highest co-citation frequency. The journal with the most published papers was "Scientific Reports," while "PLoS One" had the highest co-citation frequency. In this field of machine learning applied to renal medicine, the article "A Clinically Applicable Approach to Continuous Prediction of Future Acute Kidney Injury" by Tomasev N et al., published in NATURE in 2019, emerged as the most influential article with the highest co-citation frequency. A keyword and reference co-occurrence analysis reveals that current research trends and frontiers in nephrology are the management of patients with renal disease, prediction and diagnosis of renal disease, imaging of renal disease, and development of personalized treatment plans for patients with renal disease. "Acute kidney injury," "chronic kidney disease," and "kidney tumors" are the most discussed diseases in medical research. The field of renal medicine is witnessing a surge in the application of machine learning. On one hand, this study offers a novel perspective on applying machine learning techniques to kidney-related diseases based on bibliometric analysis. This analysis provides a comprehensive overview of the current status and emerging research areas in the field, as well as future trends and frontiers. Conversely, this study furnishes data on collaboration and exchange between countries, regions, institutions, journals, authors, keywords, and reference co-citations. This information can facilitate the advancement of future research endeavors, which aim to enhance interdisciplinary collaboration, optimize data sharing and quality, and further advance the application of machine learning in the renal field.

Origins and Molecular Mechanisms Underlying Renal Vascular Development.

Kidneys play a crucial role in maintaining homeostasis within the body, and this function is intricately linked to the vascular structures within them. For vascular cells in the kidney to mature and function effectively, a well-coordinated spatial alignment between the nephrons and complex network of blood vessels is essential. This arrangement ensures efficient blood filtration and regulation of the electrolyte balance, blood pressure, and fluid levels. Additionally, the kidneys are vital in regulating the acid-base balance and producing hormones involved in erythropoiesis and blood pressure control. This article focuses on the vascular development of the kidneys, summarizing the current understanding of the origin and formation of the renal vasculature, and the key molecules involved. A comprehensive review of existing studies has been conducted to elucidate the cellular and molecular mechanisms governing renal vascular development. Specific molecules play a critical role in the development of renal vasculature, contributing to the spatial alignment between nephrons and blood vessels. By elucidating the cellular and molecular mechanisms involved in renal vascular development, this study aims to advance renal regenerative medicine and offer potential avenues for therapeutic interventions in kidney disease.

Early Detection and Noninvasive Staging of Kidney Dysfunction by a PEGylated Conventional Fluorophore via GFR-Sensitive Renal Transport.

Noninvasive fluorescence imaging of renal function is a valuable technique for understanding kidney disease progression and the development of renal medicine. This technique requires sensitive imaging probes for reporting renal dysfunction accurately at early stage. Herein, a molecularly engineered imaging probe (800CW-PEG45-COOH) was synthesized by simply PEGylating conventional near-infrared fluorophore IRDye800CW with NH2-PEG45-COOH (molecular weight ∼2100 Da) for early detection and staging of renal dysfunction through noninvasive real-time kidney imaging. 800CW-PEG45-COOH not only cleared through the kidney efficiently (>90% injection dosage at 24 h postinjection) but was also found to be freely filtered by glomeruli without renal tubular reabsorption and secretion. Despite this simple construction strategy, the transport of 800CW-PEG45-COOH within the kidneys was extremely sensitive to the alteration of the glomerular filtration rate (GFR), which enabled it to detect renal dysfunction much earlier than commonly used serum biomarkers and stage kidney function impairments (mild vs severe dysfunction) via imaging-based kidney clearance kinetics. This work not only provides a promising optical imaging probe for the noninvasive evaluation of kidney function but also highlights the utility of PEGylation in enhancing the performance of conventional organic dyes in biomedical applications.

1004 Urgent Explant of Infected Aortic Stent Graft in a Patient with Kidney Transplant Using Biological Aortoiliac Reconstruction and a Temporary Axillo-Femoral Perfusion Shunt: 6-Year Follow-Up and Literature Review

Abstract Background Written consent obtained for case report. A 59-year-old male who was 3-months post-EVAR repair under immunosuppression for kidney transplantation and anti-retroviral HIV treatment presented to ED in 2017 with abdominal pain and fever. CTAP revealed pyelonephritis in renal allograft. Blood cultures were positive for staphylococcus epidermidis. PETCT showed high-intensity uptake around endograft. Urgent explant of endograft and insitu biological aorto-biiliac graft reconstruction with bench prepared bilateral long saphenous veins were performed. Results The predicted challenges were locating source of infection, immunosuppressed state, and allograft preservation. Dacron graft was used as temporary perfusion shunt (left axillary artery to right superficial femoral artery) for renal allograft on right external iliac vessels. Endograft was removed via rooftop incision with visceral rotation. Supra-celiac and supra-superior mesenteric artery clamping times were 15 and 35 minutes. The source of infection was from infected appendix proximal to graft with erosion of right external iliac artery resulting in appendectomy in the same operation. Following 12-weeks of OPAT antibiotic-therapy, repeat PETCT revealed low-grade uptake around aortic graft and inflammatory markers were back to baseline. At 6 years in 2023, patient remains clinically well with ∼20% allograft function. Maintaining kidney allograft perfusion in the setting of elective non-infected aortic graft explant was previously reported, but with ENROUTE system (Rasheed et al., 2018). Conclusions The satisfactory long-term outcomes discussed here demonstrated with MDT planning involving vascular surgery, infectious diseases, renal medicine and patient, explant of infected graft with insitu biological graft reconstruction in renal transplant patients presenting with complex aortic-graft infection is feasible.

The physiological basis of renal nuclear medicine.

Renal physiology underpins renal nuclear medicine, both academic and clinical. Clearance, an important concept in renal physiology, comprises tissue uptake rate of tracer (tissue clearance), disappearance rate from plasma (plasma clearance), appearance rate in urine (urinary clearance) and disappearance rate from tissue. In clinical research, steady-state plasma clearances of para-amino-hippurate and inulin have been widely used to measure renal blood flow (RBF) and glomerular filtration rate (GFR), respectively. Routinely, GFR is measured at non-steady state as plasma clearance of a filtration agent, such as technetium-99m diethylenetriaminepentaacetic acid. Scaled to three-dimensional whole body metrics rather than body surface area, GFR in women is higher than in men but declines faster with age. Age-related decline is predominantly from nephron loss. Tubular function determines parenchymal transit time, which is important in renography, and the route of uptake of technetium-99m dimercaptosuccinic acid, which is via filtration. Resistance to flow is defined according to the pressure-flow relationship but in renography, only transit time can be measured, which, being equal to urine flow divided by collecting system volume, introduces further uncertainty because the volume is also unmeasurable. Tubuloglomerular feedback governs RBF and GFR, is regulated by the macula densa, mediated by adenosine and renin, and can be manipulated with proximal tubular sodium-glucose cotransporter-2 inhibitors. Other determinants of renal haemodynamics include prostaglandins, nitric oxide and dopamine, while protein meal and amino acid infusion are used to measure renal functional reserve. In conclusion, for measuring renal responses to exogenous agents, steady-state para-amino-hippurate and inulin clearances should be replaced with rubidium-82 and gallium-68 EDTA for measuring RBF and GFR.

Pregnancy outcomes for women with pre-existing renal disease and the role of a dedicated joint maternal medicine and renal clinic: A retrospective cohort study.

Pregnancy outcomes for women with pre-existing renal disease and the role of a dedicated joint maternal medicine and renal clinic: A retrospective cohort study.

Cost-effectiveness of sodium zirconium cyclosilicate for advanced chronic kidney patients in Singapore.

Hyperkalaemia (HK) is prevalent among patients with chronic kidney disease (CKD) and chronic heart failure, especially if they are treated with renin-angiotensin-aldosterone system inhibitors (RAASi). This study evaluated the cost-effectiveness of a newly developed anti-HK therapy, sodium zirconium cyclosilicate (SZC), to the current standard of care for treating HK in advanced CKD patients from the Singapore health system perspective. We adapted a global microsimulation model to simulate individual patients' potassium level trajectories with baseline potassium ≥5.5 mmol/L, CKD progression, changes in treatment, and other fatal and non-fatal events. Effectiveness data was derived from ZS-004 and ZS-005 trials. Model parameters were localised using CKD patients' administrative and medical records at the Singapore General Hospital Department of Renal Medicine. We estimated the lifetime cost and quality-adjusted life years (QALYs) of each HK treatment, and the incremental cost-effectiveness ratio of SZC. SZC demonstrated cost-effectiveness with an incremental cost-effectiveness ratsio of SGD 45 068 per QALY over a lifetime horizon, below the willingness-to-pay threshold of SGD 90 000 per QALY. Notably, SZC proved most cost-effective for patients with less severe CKD who were concurrently using RAASi. Sensitivity analyses confirmed the robustness of the findings, accounting for alternative parameter values and statistical uncertainty. This study establishes the cost-effectiveness of SZC as a treatment for HK, highlighting its potential to mitigate the risk of hyperkalaemia and optimise RAASi therapy. These findings emphasise the value of integrating SZC into the Singapore health system for improved patient outcomes and resource allocation.

The role of depression between sleep disorders and frailty among elderly patients with chronic kidney disease (CKD) in China: a cross-sectional study.

To investigate the correlation among sleep disorders, physical frailty, and depression in elderly patients with chronic kidney disease (CKD), and to explore the mediating role of depression. This was a cross-sectional study, simple sampling was used to investigate the elderly CKD patients from one tertiary hospital in Shanghai. Those CKD patients who were diagnosed as CKD1-5 phase and were admitted to the Renal Medicine Ward from January to June 2022 and provided formal consent were considered for inclusion in our study. They were investigated with frailty phenotype (FP), Pittsburgh sleep quality index (PSQI), Center for Epidemiological Studies Depression Scale (CES-D), and self-made general information questionnaire. Linear regression was used to assess the associations between the variables, before this, PROCESS v4.1 was used to transform PSQI, CES-D and FP score to improve its normality, and conduct intermediary analysis. A difference of p < 0.05 was statistically significant. A total of 504 elderly patients with CKD completed the questionnaire survey, aged 60-91. The incidence of sleep disorders among elderly patients with CKD was 60%, and the incidence of physical frailty was 18%. The depression was positively correlated with physical frailty (r = 0.418, p < 0.01) and sleep disorders (r = 0.541, p < 0.01). Physical frailty was positively correlated with sleep disorders (r = 0.320, p < 0.01). The depression plays a significant mediating role in the model, and the effect ratio of depression is 52%. Depression is a mediating variable between sleep disorders and frailty. Improving depression in elderly patients with CKD accompanied by sleep disorders can help delay the occurrence of frailty.

Anthony Eisinger: innovative nephrologist who established a centre of excellence in renal medicine

Anthony Eisinger: innovative nephrologist who established a centre of excellence in renal medicine

P25 Nowhere to hide: broad-spectrum antimicrobial guideline adherence in outpatients

Abstract Background The NHS Acute Trusts Standard1 contract requires a 10% reduction in broad-spectrum antibiotics by 10% by March 2024 from a 2017 baseline. Co-amoxiclav is a broad-spectrum antibacterial that comprises 30% of broad-spectrum consumption at University Hospitals Birmingham. It is widely used across all specialities and is a perfect candidate to review to influence downward trend in consumption. Outpatient prescriptions do not receive the same level of scrutiny from pharmacy or antimicrobial stewardship team as inpatient prescriptions. If deviations from guidelines are identified, then this could be a potential area to address to reduce consumption. Methods Sixty outpatient co-amoxiclav prescriptions were reviewed to assess appropriateness of prescribing during December 2022. Parameters assessed included the indication and duration of co-amoxiclav therapy and adherence to Trust antimicrobial guidelines. The speciality prescribing outpatient co-amoxiclav was also documented to identify whether prescribing trends could be identified. Results Of 60 reviewed outpatient prescriptions written in December 2022, 54 were issued by acute medicine with other specialities including cardiothoracic, renal medicine, elderly care, ENT, urology and cardiology. All prescriptions had a documented indication and duration, however only three were adherent to Trust antimicrobial guidelines. The graph below represents the different indications co-amoxiclav was prescribed for to outpatients across all three hospital sites. Co-amoxiclav was most frequently prescribed for respiratory tract infections, followed by skin and then urinary tract infections. Conclusions This audit has highlighted that outpatient co-amoxiclav is commonly prescribed inappropriately and does not comply with Trust antimicrobial guidelines. The speciality most frequently prescribing outpatient co-amoxiclav inappropriately was acute and emergency medicine. The lack of clarity regarding the infection indication is a potentially important factor in this setting, resulting in broad-spectrum antimicrobial use to cover multiple potential bacterial infections. A limitation of this audit is it was carried out over a short and busy winter period.

Three-Dimensional Printing and Bioprinting in Renal Transplantation and Regenerative Medicine: Current Perspectives.

For patients with end-stage kidney disease (ESKD), renal transplantation is the treatment of choice, constituting the most common solid organ transplantation. This study aims to provide a comprehensive review regarding the application of three-dimensional (3D) printing and bioprinting in renal transplantation and regenerative medicine. Specifically, we present studies where 3D-printed models were used in the training of surgeons through renal transplantation simulations, in patient education where patients acquire a higher understanding of their disease and the proposed operation, in the preoperative planning to facilitate decision-making, and in fabricating customized, tools and devices. Three-dimensional-printed models could transform how surgeons train by providing surgical rehearsal platforms across all surgical specialties, enabling training with tissue realism and anatomic precision. The use of 3D-printed models in renal transplantations has shown a positive impact on surgical outcomes, including the duration of the operation and the intraoperative blood loss. Regarding 3D bioprinting, the technique has shown promising results, especially in the field of microfluidic devices, with the development of tissue demonstrating proximal tubules, glomerulus, and tubuloinerstitium function, and in renal organoid development. Such models can be applied for renal disease modeling, drug development, and renal regenerative medicine.

Performance and limitations of a supervised deep learning approach for the histopathological Oxford Classification of glomeruli with IgA nephropathy

Background and ObjectiveThe Oxford Classification for IgA nephropathy is the most successful example of an evidence-based nephropathology classification system. The aim of our study was to replicate the glomerular components of Oxford scoring with an end-to-end deep learning pipeline that involves automatic glomerular segmentation followed by classification for mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental sclerosis (S) and active crescents (C). MethodsA total number of 1056 periodic acid–Schiff (PAS) whole slide images (WSIs), coming from 386 kidney biopsies, were annotated. Several detection models for glomeruli, based on the Mask R-CNN architecture, were trained on 587 WSIs, validated on 161 WSIs, and tested on 127 WSIs. For the development of segmentation models, 20,529 glomeruli were annotated, of which 16,571 as training and 3958 as validation set. The test set of the segmentation module comprised of 2948 glomeruli. For the Oxford classification, 6206 expert-annotated glomeruli from 308 PAS WSIs were labelled for M, E, S, C and split into a training set of 4298 glomeruli from 207 WSIs, and a test set of 1908 glomeruli. We chose the best-performing models to construct an end-to-end pipeline, which we named MESCnn (MESC classification by neural network), for the glomerular Oxford classification of WSIs. ResultsInstance segmentation yielded excellent results with an AP50 ranging between 78.2–80.1 % (79.4 ± 0.7 %) on the validation and 75.1–77.7 % (76.5 ± 0.9 %) on the test set. The aggregated Jaccard Index was between 73.4–75.9 % (75.0 ± 0.8 %) on the validation and 69.1–73.4 % (72.2 ± 1.4 %) on the test set. At granular glomerular level, Oxford Classification was best replicated for M with EfficientNetV2-L with a mean ROC-AUC of 90.2 % and a mean precision/recall area under the curve (PR-AUC) of 81.8 %, best for E with MobileNetV2 (ROC-AUC 94.7 %) and ResNet50 (PR-AUC 75.8 %), best for S with EfficientNetV2-M (mean ROC-AUC 92.7 %, mean PR-AUC 87.7 %), best for C with EfficientNetV2-L (ROC-AUC 92.3 %) and EfficientNetV2-S (PR-AUC 54.7 %). At biopsy-level, correlation between expert and deep learning labels fulfilled the demands of the Oxford Classification. ConclusionWe designed an end-to-end pipeline for glomerular Oxford Classification on both a granular glomerular and an entire biopsy level. Both the glomerular segmentation and the classification modules are freely available for further development to the renal medicine community.

Proteinuria as a Surrogate Endpoint for Disease Progression in IgA Nephropathy: Predicting Long-Term Treatment Effects of Sparsentan

IgA nephropathy (IgAN) is a rare, life-limiting disease for which there is significant unmet need. Until recently, drug development for IgAN had been impeded by the requirement for large-scale, long-term clinical trials to measure clinical outcomes. However, the recent establishment of ‘reduction in proteinuria’ as a surrogate endpoint to predict clinical outcomes in IgAN, as a basis for accelerated drug approval, has transformed the field. At the 60th European Renal Association (ERA) Congress in June 2023, two oral poster presentations focused on the use of early reduction in proteinuria as an endpoint for clinical studies in IgAN. Alex Mercer, Consultant in Clinical Drug Development at JAMCO Pharma Consulting in Stockholm, Sweden, presented data estimating the long-term clinical outcome of reductions in proteinuria (clinically meaningful extensions in time to kidney failure or death), which could help predict the future protective effect of any new intervention on kidney function. Following this, Jonathan Barratt, Mayer Professor of Renal Medicine at the University of Leicester, and Honorary Consultant Nephrologist at Leicester General Hospital, UK, described findings from the prespecified interim analysis of the Phase III PROTECT study of sparsentan (a novel dual endothelin angiotensin receptor antagonist) in IgAN, which included reduction in proteinuria as a primary endpoint. In patients with IgAN at high risk of disease progression, sparsentan produced a rapid and significant reduction in proteinuria of a level that, according to the study data presented by Mercer, would correspond to a substantially lowered risk of kidney failure or death. Long-term data to confirm this predicted clinical outcome on disease progression are anticipated.

#5790 IMPAIRED FATTY ACID METABOLISM PERPETUATES LIPOTOXICITY ALONG THE TRANSITION TO CHRONIC KIDNEY INJURY

Abstract Background and Aims Understanding the cell-intrinsic mechanisms contributing to the maintenance of a dysfunctional cellular state in chronic kidney disease (CKD) and identifying therapeutic targets are research priorities in renal medicine. A key contributor to chronic kidney histological damage is acute kidney injury, especially ischemia-reperfusion injury (IRI). Persistent cell-extrinsic perturbations generated upon IRI, for example hypoxia, impair the energetic metabolism of Proximal Tubular Cells (PTC) participating in the process of transition from acute to chronic kidney injury. Here, we propose to investigate the PTC intrinsic factors involved in the perpetuation of an impaired cellular state which contribute to CKD progression Method We combined single nucleus transcriptomic, metabolomic and lipidomic approaches in experimental models and patient cohorts to investigate the molecular bases of the progression to chronic kidney allograft injury initiated by IRI. Results The urinary metabolome of kidney transplant recipients with chronic allograft injury and who experienced severe IRI was significantly enriched with long chain fatty acids (FA). We identified a renal FA-related gene signature with low levels of Cpt2 and Acsm5 and high levels of Acsl4 and Acsm5 associated with IRI, transition to chronic injury, and established CKD in mouse models and kidney transplant recipients. The findings were consistent with the presence of Cpt2-, Acsl4+, Acsl5+, Acsm5- PTC failing to recover from IRI as identified by single nucleus RNA sequencing. In vitro experiments indicated that endoplasmic reticulum (ER) stress contributes to CPT2 repression, which, in turn, promotes lipids accumulation, drives profibrogenic epithelial phenotypic changes, and activates the unfolded protein response. Conclusion ER stress through CPT2 inhibition and lipid accumulation, engages an auto-amplification loop leading to lipotoxicity and self-sustained cellular stress. Thus, IRI imprints a persistent FA metabolism disturbance in the proximal tubule sustaining the progression to chronic kidney allograft injury.