Kidney international最新文献

{"title":"Evaluation of Methodologies in Anti-nephrin Autoantibody Detection.","authors":"Pan Liu, Shuping Liu, Vidhi Dalal, Jerome Lane, Paolo Cravedi, Kirk Campbell, Andrea Angeletti, Xinfang Xie, Elisa Gessaroli, Eleonora Forte, Lorenzo Gallon, Jing Jin","doi":"10.1016/j.kint.2025.05.018","DOIUrl":"https://doi.org/10.1016/j.kint.2025.05.018","url":null,"abstract":"<p><strong>Introduction: </strong>Recent studies discovered the prominent presence of anti-nephrin autoantibodies in minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). However, widely different, and often unconventional autoantibody detection methods were used in these studies, making it challenging to standardize anti-nephrin antibody detection and quantification across different studies.</p><p><strong>Methods: </strong>Here, we compare methods of conventional ELISA, immunoprecipitation (IP)- based on-beads ELISA, immunoprecipitation-Western blotting (IP-WB), and cell- and tissue-based immunofluorescence staining with two cohorts totaling 169 patients and control individuals.</p><p><strong>Results: </strong>Different assay methods and antigen preparations led to method-specific false-positive and false-negative results. In general, high-quality antigens produced in human cells, combined with IP-based assays, yielded the most robust and reliable results. Among 63 and 24 samples from patients with FSGS or MCD, respectively, two patients with FSGS showed strong antibody signals in both ELISA-based assays and IP-WB, while approximately half of patients with MCD had weak signals detectable only by IP-WB.</p><p><strong>Conclusion: </strong>These findings highlight the importance of standardizing antibody detection methods.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phospholipase A2receptor-positive membranous nephropathy detected by laser microdissection and mass spectrometry in patients negative by immunofluorescence for phospholipase A2receptor on kidney biopsy.","authors":"Ladan Zand, Ilario Russo, Maria J Vargas-Brochero, Samih H Nasr, Benjamin Madden, Jason D Theis, Fernando C Fervenza, Sanjeev Sethi","doi":"10.1016/j.kint.2025.04.032","DOIUrl":"https://doi.org/10.1016/j.kint.2025.04.032","url":null,"abstract":"<p><strong>Introduction: </strong>Membranous Nephropathy (MN) is characterized by subepithelial deposition of immune complexes along the glomerular basement membrane. The muscle-type phospholipase A2 receptor (PLA2R) has been identified as the principal antigen in MN, and its detection via immunofluorescence (IF) studies remains a diagnostic cornerstone. Advancements, including Laser Microdissection/Mass Spectrometry (LMD/MS), offer enhanced sensitivity for antigen identification, independent of epitope accessibility.</p><p><strong>Methods: </strong>A cohort of 250 kidney biopsy samples (discovery cohort) diagnosed as PLA2R-negative MN by IF underwent LMD/MS analysis for antigen detection. Biopsies were microdissected, and peptides were analyzed using high-performance liquid chromatography coupled with mass spectrometry. Total spectral counts greater than 10 are considered positive for PLA2R-associated MN.</p><p><strong>Results: </strong>LMD/MS identified PLA2R antigen in seven (2.8%) cases classified as PLA2R-negative by IF. The mean total spectral count in the seven cases was 55. Additionally, LMD/MS detected another two positive cases in PLA2R-negative MN from a recently validated clinical test for antigen detection. The mean total spectral count in these two cases was 189. All nine cases showed significant IgG along the glomerular basement membrane. Electron microscopy showed stage II MN in seven of the nine cases, one case showed stage I, and the other showed stage III-IV MN. Serologic studies showed anti-PLA2R antibodies in two of seven cases with available data.</p><p><strong>Conclusion: </strong>A small subset of PLA2R-negative MN by IF became PLA2R-positive by LMD/MS. Our study emphasizes the importance of not ruling out the possibility of PLA2R-associated MN in patients with negative IF staining for PLA2R. LMD/MS is an important diagnostic test for MN antigen detection.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemical chaperone 4-phenylbutyrate treatment alleviates the kidney phenotype in a mouse model of Alport syndrome with a pathogenic variant in Col4a3.","authors":"Pavlos Ioannou, Christoforos Odiatis, Rania Hadjisavva, Kyriaki Antoniadou, Myrtani Pieri, Apostolos Malatras, Gregory Papagregoriou, Antrea Aristotelous, Paris Skourides, Martina Samiotaki, Matija Horaček, Danica Galešić Ljubanović, Kostas Stylianou, Constantinos Deltas","doi":"10.1016/j.kint.2025.05.016","DOIUrl":"https://doi.org/10.1016/j.kint.2025.05.016","url":null,"abstract":"<p><strong>Introduction: </strong>Alport Syndrome is a severe inherited glomerulopathy caused by pathogenic variants in genes encoding collagen-IV, the most abundant component of the glomerular basement membrane. Patients with Alport lack effective therapies beyond blockade of the renin-angiotensin-aldosterone system. Here, we test 4-phenylbutyrate (4-PBA) and tauroursodeoxycholic acid (TUDCA), two chemical chaperones, to rescue mouse models of a later-onset Alport Syndrome.</p><p><strong>Methods: </strong>Knock-in mice bearing the Col4a3:p.Gly1332Glu pathogenic substitution in homozygosity and a compound heterozygous model bearing the same variant and the knockout allele were used. Mice received chaperones either for short or long-term periods. Also. we examined the expression and secretion of mutant α3 chains in primary cultured mouse podocytes.</p><p><strong>Results: </strong>TUDCA-treated Alport mice did not differ from the placebo-treated group. However, mice treated with 4-PBA demonstrated considerable improvement in the morphology and structure of glomerular basement membranes compared with control placebo-treated mice. Electron microscopy showed a 54% reduction of lesions and significant decline of lesion severity in the basement membrane of treated Alport mice. Additionally, treatment with 4-PBA reduced interstitial fibrosis, global and segmental glomerulosclerosis, while proteinuria and hematuria remained at low levels in Alport mice. In-vivo findings and in-vitro inhibition of the proteasome in primary cultured podocytes indicate that mutant collagen is reduced within the glomeruli of mutant mice, likely due to proteasomal degradation of misfolded collagen. Importantly, treatment of mice and cultured podocytes with 4-PBA improved secretion and incorporation of collagen IV into extracellular matrix probably by enhancing trimer folding.</p><p><strong>Conclusions: </strong>Our results suggest a therapeutic potential for 4-PBA in combating kidney dysfunction in Alport syndrome.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multicenter prospective cohort study evaluating impact of an active delisting strategy to enable kidney transplantation in wait-listed candidates with calculated Panel Reactive Antibody ≥ 99.9.","authors":"David Cucchiari, Esther Mancebo-Sierra, José Luis Caro, Maria Meneghini, María José Pérez-Saez, Beatriz Romero López, Dolores Redondo-Pachón, Carolt Arana, Oriol Bestard, Amado Andrés, Francesc Moreso, Marta Crespo, Eduard Palou, Fritz Diekmann","doi":"10.1016/j.kint.2025.04.031","DOIUrl":"https://doi.org/10.1016/j.kint.2025.04.031","url":null,"abstract":"<p><strong>Introduction: </strong>In kidney transplant candidates with calculated Panel Reactive Antibody (cPRA)≥99.9%, looking for perfect HLA compatibility may delay transplantation beyond a reasonable waiting time. However, the presence of preformed donor-specific antibody (DSA) does not always lead to antibody-mediated rejection. Here, we present the results of a delisting strategy for kidney transplant candidates with cPRA≥99.9% employed in four Spanish transplant centers May 2022-August 2023.</p><p><strong>Methods: </strong>Briefly, HLA antigens were delisted if their mean fluorescence intensity (MFI) in current and historical samples was lower than 5,000, with the goal to decrease cPRA to ≤99.0%. If this first step was unsuccessful, HLA antibodies with an MFI under10,000, or any MFI for anti-HLA-DP and anti-HLA-DRB3/4/5 were considered for delisting. Additional criteria included their 1/16 dilutions response and complement-binding activity (C3d or C1q), ideally avoiding antibodies targeting a cross-reactive epitope groups/eplet pattern and repeated mismatches with previous donors.</p><p><strong>Results: </strong>In total, 48 patients underwent HLA-antigen delisting after a median 5.6 years on the waiting list, lowering their cPRA to 98.3%. Thirty (62.5%) patients received an acceptable donor offer 98[52-154] days after delisting, of which 18 (60.0%) had negative flow cytometry and complement-dependent cytotoxicity crossmatches and underwent direct transplantation without additional desensitization with the enzyme imlifidase. Among these, sixteen patients (83.3%) had at least one preformed DSA, with an immunodominant MFI of 7245[3857-18322]. In these patients, after one-year follow-up, antibody-mediated rejection occurred in seven cases (43.7%) and graft survival was 87.5%.</p><p><strong>Conclusions: </strong>Our study shows that careful antigen delisting enhances access to transplantation for patients with cPRA ≥99.9%. While this approach carries a significant risk of acute rejection, it is associated with reasonable short-term graft survival.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zigakibart demonstrates clinical safety and efficacy in a Phase 1/2 trial of healthy volunteers and patients with IgA nephropathy.","authors":"Laura Kooienga, Eun Young Lee, Sung Gyun Kim, Hannah Thomas, Biruh Workeneh, Irfan Agha, Yuanbo Song, William Smith, Hans van Eenennaam, Andrea Van Elsas, John Dulos, Jonathan Barratt","doi":"10.1016/j.kint.2025.05.006","DOIUrl":"https://doi.org/10.1016/j.kint.2025.05.006","url":null,"abstract":"<p><strong>Introduction: </strong>Zigakibart is a humanized IgG4 monoclonal antibody that binds the cytokine A Proliferation-Inducing Ligand (APRIL also known as TNFSF13). APRIL is a critical factor in immunoglobulin (Ig) A nephropathy (IgAN) pathogenesis.</p><p><strong>Methods: </strong>Here, we report healthy volunteer (63 overall) and 100-week data from an ongoing Phase 1/2 clinical trial in 40 patients with IgAN (NCT03945318) treated with zigakibart.</p><p><strong>Results: </strong>In health volunteers, zigakibart was well tolerated following intravenous administration of single doses ranging from 10-1350 mg or multiple doses ranging from 50-450 mg every two weels. Zigakibart exposure increased in a dose-proportional manner, with corresponding durable reductions in levels of free APRIL, IgA and IgM, and to a lesser extent, IgG. In patients with IgAN, zigakibart 600 mg, administered subcutaneously every two weeks, was well tolerated with no treatment-emergent adverse events leading to study drug discontinuation or death. A 60% reduction in proteinuria and sustained estimated glomerular filtration rate stabilization was observed at week 100. There was a notable decrease in hematuria, as well as rapid and durable reductions in IgA, galactose-deficient IgA (Gd-IgA1), and IgM levels, with a modest reduction in IgG.</p><p><strong>Conclusions: </strong>Overall, zigakibart demonstrated robust pharmacological activity, and clinical evidence shows an acceptable safety profile with clinically meaningful proteinuria reduction and sustained estimated glomerular filtration rate stabilization in patients with IgAN, providing a potentially disease-modifying approach for the treatment of IgAN. The effects of zigakibart on proteinuria and long-term kidney function in adults with IgAN are being evaluated in the ongoing Phase 3 BEYOND study (NCT05852938).</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The enzyme SMPDL3b in podocytes decouples proteinuria from chronic kidney disease progression in experimental Alport Syndrome.","authors":"Alla Mitrofanova, Antonio M Fontanella, Judith Molina, Guanshi Zhang, Shamroop K Mallela, Luisa Ulloa Severino, Javier Varona Santos J, Matthew Tolerico, Rachel Njeim, Wadih Issa, Maria Boulina, Arianna Carrazco, Veronika Semenova, Yiqin Zuo, Maria Ficarella, Jin Ju Kim, Alexis Sloan, Kumar Sharma, Darren A Yuen, Laura Perin, George W Burke, Alessia Fornoni, Sandra Merscher","doi":"10.1016/j.kint.2025.04.024","DOIUrl":"https://doi.org/10.1016/j.kint.2025.04.024","url":null,"abstract":"<p><strong>Background: </strong>Chronic kidney disease, including Alport Syndrome, is linked to collagen type IV mutations, lipid dysmetabolism, and altered sphingolipid pathways, with no targeted therapies currently available. Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b), a key regulator of sphingolipid metabolism and membrane receptor organization in podocytes, may drive disease via ceramide and sphingosine-1-phosphate pathways. This study tested whether altered SMPDL3b expression contributes to glomerular injury and renal decline in Alport Syndrome.</p><p><strong>Methods: </strong>Archived Alport Syndrome human biopsies were used for immunohistochemistry and NanoString re-analysis of SMPDL3b. Murine podocytes isolated from mouse models of Alport Syndrome were profiled using Illumina. Mouse models of Alport Syndrome and models with either podocyte-specific deletion or inducible overexpression of Smpdl3b were generated to assess renal function using liquid chromatography-mass spectrometry, matrix-assisted laser desorption ionization-mass spectrometry imaging and atomic force microscopy.</p><p><strong>Results: </strong>We found a three-fold increase in SMPDL3b expression in glomeruli, tubules and murine podocytes isolated from Col4a3 knockout mice. Increased SMPDL3b expression occurred in association with alterations affecting kidney sphingolipid metabolism, increased glomerular but not tubular sphingosine-1-phosphate levels and reduced glomerular basement membrane and podocyte stiffness. Podocyte-specific Smpdl3b deletion in Col4a3 knockout mice was sufficient to restore sphingosine-1-phosphate levels, to reduce proteinuria, podocyte foot process effacement, and improve glomerular basement membrane and podocyte stiffness, but not sufficient to protect from kidney failure.</p><p><strong>Conclusions: </strong>Our study suggests that SMPDL3b may be a key modulator of proteinuria and podocyte integrity in Alport Syndrome, decoupling proteinuria from kidney failure, and suggests that improvement of glomerular structure and function may not always translate into protection from chronic kidney disease progression.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Women and kidney health: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.","authors":"Giorgina Barbara Piccoli, Sofia B Ahmed, Fadi Fakhouri, Vesna D Garovic, Michelle A Hladunewich, Shilpanjali Jesudason, Jai Prakash, Angela C Webster, Elena Zakharova, Michael Cheung, Jennifer M King, Michel Jadoul, Wolfgang C Winkelmayer, Christina M Wyatt","doi":"10.1016/j.kint.2025.02.021","DOIUrl":"10.1016/j.kint.2025.02.021","url":null,"abstract":"<p><p>The KDIGO (Kidney Disease: Improving Global Outcomes) Controversies Conference on Women and Kidney Health was convened to identify key sex and gender issues in kidney care, practices for optimizing healthcare in women with kidney diseases, and priorities for future research. Participants emphasized the importance of addressing the influence of sex and gender in diagnosis, risk assessment, prognosis, and treatment of chronic kidney disease (CKD) and its complications, as well as considering issues across the lifespan (puberty, sexual and reproductive health, menopause). CKD is a risk factor for adverse pregnancy outcomes with every type of kidney disease and severity. All women of reproductive age known to have CKD should be counseled on contraception, the ideal timing of pregnancy, the risks and outcomes for mother and fetus, fertility treatments where these are available, medication management, and medical aspects of pregnancy termination. A successful pregnancy is possible across all severities of CKD, including in women living with dialysis or a kidney transplant. Pregnancy should be managed with a multidisciplinary care plan based upon the type of kidney disease and the presence and severity of kidney function impairment, hypertension, and proteinuria. Systematic assessment of blood pressure, proteinuria, and kidney function in all pregnancies would facilitate diagnosis of CKD and detection of acute kidney injury (AKI). Follow-up programs for women who experienced pregnancy-related AKI, preeclampsia, or other hypertensive disorders of pregnancy are important as these conditions may reflect undiagnosed CKD and have important implications for future cardiovascular health.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":14.8,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A randomized controlled trial of intravenous immunoglobulin vs standard of care for the treatment of chronic active antibody-mediated rejection in kidney transplant recipients.","authors":"William R Mulley,Dhakshayini Tharmaraj,Kevan R Polkinghorne,Greg H Tesch,Sukhpal K Dayan,Edward Kwan,Moshe Olshansky,Tia Mark,Darren Lee,Peter F Mount,Germaine Wong,Kate R Wyburn,Wai H Lim,Peter G Kerr,David J Nikolic-Paterson,John Kanellis","doi":"10.1016/j.kint.2025.04.023","DOIUrl":"https://doi.org/10.1016/j.kint.2025.04.023","url":null,"abstract":"INTRODUCTIONChronic active antibody-mediated rejection (AMR) is the leading cause of death-censored kidney allograft loss, with no proven treatments. While intravenous immunoglobulin (IVIG) has been used in certain cases, its efficacy is unknown.METHODSIn this open-label multicenter randomized controlled trial (VIPAR), participants with biopsy-proven chronic active AMR, were assigned to six doses (1g/kg/month) of IVIG or no-IVIG. The primary endpoint was the difference in slopes of the chronic allograft damage index (CADI) scores between groups, across four allograft biopsies (baseline, three, six and 12-months). Secondary outcomes, assessed at baseline, three, six and 12-months, included change in estimated glomerular filtration rate (eGFR), change in donor specific anti-HLA antibodies (DSA), allograft and patient survival, and change in intra-graft mRNA expression.RESULTSFifteen participants were randomized to each arm. Their median age was 54.3 years, 22 were male and mean eGFR was 43.3 ml/min/1.73m2. Participants in the no-IVIg group experienced a significant increase in mean CADI (+0.28/month, 95% confidence interval 0.14 to 0.41), while the IVIG group did not (-0.004/month, - 0.13 to 0.12). Over two years, eGFR significantly declined more rapidly in the no-IVIG group (-1.1 ml/min/month, -1.5 to -0.7 ml/min/month) than the IVIG group (-0.4 ml/min/month, - 0.8 to 0.03 ml/min/month). Differences in patient and allograft survival were not evident by 12 months. Intra-graft expression of 59 genes (mostly B-cell related) reduced with IVIG relative to no-IVIG.CONCLUSIONIVIG therapy was associated with stabilization in allograft histology and eGFR in kidney transplant recipients with chronic active AMR.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"3 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical relevance of computationally derived tubular features and their spatial relationships with the interstitial microenvironment in minimal change disease/focal segmental glomerulosclerosis.","authors":"Fan Fan,Qian Liu,Jarcy Zee,Takaya Ozeki,Dawit Demeke,Yingbao Yang,Markus Bitzer,Christopher L O'Connor,Alton B Farris,Bangcheng Wang,Manav Shah,Jackson Jacobs,Laura Mariani,Kyle Lafata,Jeremy Rubin,Yijiang Chen,Lawrence Holzman,Jeffrey B Hodgin,Anant Madabhushi,Laura Barisoni,Andrew Janowczyk","doi":"10.1016/j.kint.2025.04.026","DOIUrl":"https://doi.org/10.1016/j.kint.2025.04.026","url":null,"abstract":"BACKGROUNDVisual scoring of tubular damage has limitations in capturing the full spectrum of structural changes and prognostic potential. Here, we investigated if computationally quantified tubular features can enhance prognostication and reveal spatial relationships with interstitial fibrosis.METHODSDeep-learning and image-analysis approaches were employed on 254/266 Periodic acid Schiff-stained whole slide image (WSI) kidney biopsies from participants in the NEPTUNE/CureGN prospective observational cohort studies (135/153 with focal segmental glomerulosclerosis (FSGS) and 119/113 with minimal change disease (MCD)) to segment cortex, tubular lumen (TL), epithelium (TE), nuclei (TN), and basement membrane (TBM). One hundred four pathomic features were extracted from these segmented tubular substructures and aggregated at the patient level using summary statistics. In the NEPTUNE dataset, tubular features were quantified at the WSI level and in manually segmented regions of mature interstitial fibrosis and tubular atrophy (IFTA), pre-IFTA, and non-IFTA. Minimum Redundancy Maximum Relevance was then used to select features most associated with disease progression and proteinuria remission. Ridge-penalized Cox models evaluated their predictive discrimination compared to clinical/demographic data and visual-assessment. Models were evaluated in the CureGN dataset.RESULTSNine features were predictive of disease progression and/or proteinuria remission. Models with tubular features had high prognostic accuracy in both NEPTUNE and CureGN, and higher prognostic accuracy for both outcomes compared to conventional parameters alone in NEPTUNE. TBM thickness/area and TE flattening and/or reduced cell size progressively increased from non- to pre- and mature IFTA.CONCLUSIONSPreviously underrecognized computationally derived and quantifiable tubular characteristics may contribute to improving prognostic accuracy and risk stratification in patients with FSGS/MCD. Future studies are needed to test their generalizability across different diseases and populations before they can be deployed in clinical practice.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"3 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144130742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Restoration of branched chain amino acid catabolism improves kidney function in preclinical cardiovascular-kidney-metabolic syndrome models.","authors":"Eliza Bollinger,George Williams,Mary E Piper,Kimberly Steen,Kelly Tam Neale,Xian Chen,Mackenzie Marshall,Srinath Jagarlapudi,Yasaman Jami-Alahmadi,Pierre M Jean-Beltran,LouJin Song,Joshua Chiou,Frank Geoly,Sarah R Vargas,Ying Zhang,Elaine Kuang,Daniel Callahan,John C Stansfield,Max Russo,John Griffin,Zhongyuan Sun,Melissa R Miller,Craig L Hyde,Michelle F Clasquin,Katherine Hales,Natalie A Daurio,Justin D Crane,Dinesh Hirenallur-Shanthappa,John Groarke,Bei B Zhang,Rachel J Roth Flach","doi":"10.1016/j.kint.2025.04.025","DOIUrl":"https://doi.org/10.1016/j.kint.2025.04.025","url":null,"abstract":"INTRODUCTIONPatients with metabolic syndrome and heart failure (HF) often have accompanying kidney dysfunction, which was recently defined as cardiovascular-kidney-metabolic (CKM) syndrome. Prior metabolomics profiling of metabolic syndrome patients identified a plasma branched chain amino acid (BCAA) signature, and BCAAs themselves are elevated in the myocardium of patients with HF, potentially due to a defect in BCAA catabolic breakdown. The rate limiting step of BCAA catabolism is the decarboxylation by the enzyme branched chain ketoacid dehydrogenase (BCKDH), which is negatively regulated by BCKDH kinase (BCKDK or BDK), and BDK inhibitors improve metabolism and heart failure preclinically.METHODSHere, using two pre-clinical CKM models, the hyperphagic ZSF1 obese rat and the uninephrectomized SDT fatty rat with high salt drinking water, we show that BCAA catabolic impairment is associated with and may be causal to CKM. Unbiased proteomic, transcriptomic and metabolomic profiling demonstrated impairment in BCAA catabolism within ZSF1 obese rat kidneys.RESULTSIn both CKM animal models, treatment with the BDK inhibitor BT2 improved urine protein content, kidney hypertrophy, and kidney pathology. Furthermore, coadministration of BT2 and the sodium-glucose cotransporter-2 inhibitor empagliflozin demonstrated additive effects to improve kidney parameters, kidney gene expression signatures, and kidney mitochondrial density and function.CONCLUSIONSOur study suggests that in addition to its previously reported effects on metabolism and cardiac function, BDK inhibition may also improve kidney health and therefore could represent a new therapeutic avenue for CKM.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"47 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144130739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}