Kidney international最新文献

{"title":"An individual patient meta-analysis assessed the associations between change in albuminuria and acute changes in the glomerular filtration rate in randomized controlled trials of chronic kidney disease progression","authors":"Lesley A. Inker MD MS, Hiddo J.L. Heerspink PhD, Hocine Tighiouart MS, Shiyuan Miao MS, Juhi Chaudhari MPH, Lucia Del Vecchio MD, Jürgen Floege MD, Thierry Hannedouche MD PhD, Enyu Imai MD, Tazeen H. Jafar MBBS, Julia B. Lewis MD, Philip K.T. Li MD FRCP, Francesco Locatelli MD, Bart D. Maes PhD, Brendon L. Neuen MBBS PhD, Ronald D. Perrone MD, Francesco P. Schena MD, Robert D. Toto MD, Christoph Wanner MD, Tom Greene PhD","doi":"10.1016/j.kint.2026.08.030","DOIUrl":"https://doi.org/10.1016/j.kint.2026.08.030","url":null,"abstract":"Early changes in albuminuria and glomerular filtration rate (GFR) have been proposed as markers of treatment efficacy for individual patients. Here, we evaluated the relationship between changes in GFR and in albuminuria in the immediate period following initiation of medication across trials and within individual patients.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"55 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149084296","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":"Prospective 96-week study to evaluate efficacy and safety of tacrolimus and glucocorticoid against mycophenolate and glucocorticoid as continuous induction-maintenance treatment for Class III/IV without or with Class V lupus nephritis.","authors":"Desmond Y H Yap, Sandra V Navarra, Zhaohui Ni, Yingyos Avihingsanon, Soo Kun Lim, Hui Zhi, Tsutomu Takeuchi, Seng Teck A Liew, Shirley C W Chan, Catherine Chan, Jiaxin S Wu, Na Jiang, Wen Jiun Liu, Wei Chen, Chao Li, Chenzhu Zhang, Ma Theresa M Collante, Leonid Zamora, Jun Kikuchi, Susan Yung, Tak Mao Chan","doi":"10.1016/j.kint.2026.08.026","DOIUrl":"https://doi.org/10.1016/j.kint.2026.08.026","url":null,"abstract":"<p><strong>Introduction: </strong>We conducted a prospective Asian multicenter randomized controlled trial to evaluate the efficacy and safety of tacrolimus (TAC) and glucocorticoid (GC), against standard-of-care mycophenolate (MMF) and GC, as continuous induction-maintenance therapy for active lupus nephritis (LN) (ClinicalTrials.gov ID: NCT02630628).</p><p><strong>Methods: </strong>One Hundred thirty biopsy-proven patients with Class III/IV without or with Class V LN were randomized to receive GC (intravenous methylprednisolone for three days then oral prednisolone) with either TAC (target trough level 6 - 8ng/mL) or MMF (1g twice a day) for 96 weeks. Primary endpoint was Sustained Renal Response (SRR) at week 96, defined as proteinuria reduction over 50% and estimated glomerular filtration rate no less than 60mL/min per 1.73m², and no disease flare or rescue therapies. Secondary endpoints included rates of Complete Renal Remission (CRR) and Partial Renal Remission (PRR) at week 96, SRR at week 48, and adverse events (AE).</p><p><strong>Results: </strong>TAC and MMF groups (65 patients each) showed no significant difference in the rates of SRR (58.5% vs 69.2% respectively) and CRR (55.4% vs 63.1% respectively) at week 96. SRR rates for TAC and MMF groups were 63.1% vs 66.2% at week 48, respectively. Overall, AE rates did not differ between TAC and MMF groups (80.0% in both). Acute kidney injury and tremors were more frequent in TAC group, while leucopoenia was more frequent in MMF group. Three deaths occurred, all in the MMF group. Treatment-related serious adverse events (SAE) and infection resulting in SAE were significantly more frequent in the MMF group.</p><p><strong>Conclusions: </strong>Dual immunosuppressive regimen with TAC and GC showed no difference in efficacy but different safety profile compared with MMF and GC over 96 weeks, when used as continuous induction-maintenance treatment for LN.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075207","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":"Podocyte GIT1 and GIT2 ArfGAPs cooperatively sustain the ARHGEF7-Cdc42 axis and glomerular permselectivity.","authors":"Jun Matsuda, Maho Tokuchi, Naoyuki Shimada, Kana Asano-Matsuda, Hiromitsu Miyakawa, Lamine Aoudjit, Claire E Martin, Tomoko Takano, Yoshitaka Isaka","doi":"10.1016/j.kint.2026.08.029","DOIUrl":"https://doi.org/10.1016/j.kint.2026.08.029","url":null,"abstract":"<p><strong>Introduction: </strong>Podocytes are specialized glomerular epithelial cells characterized by actin-rich projections known as foot processes, which are essential for maintaining the filtration barrier. The Rho-family small GTPases Rac1 and Cdc42 are key regulators of actin cytoskeletal dynamics in podocytes, influencing cell adhesion, polarity and survival. However, the regulatory mechanisms of Rho GTPase activities in foot processes remain poorly understood. We previously identified GIT ArfGAP2 (GIT2) as a protective protein in podocytes that suppresses Rac1 activity at focal adhesions. However, the role of its paralog, GIT ArfGAP1 (GIT1), is unknown.</p><p><strong>Methods: </strong>To study this, podocyte-specific GIT1 deficient and GIT1/GIT2 double deficient mice were generated and assessed for glomerular phenotypes. Cultured podocytes with GIT1/GIT2 single or double knockdown were established and characterized.</p><p><strong>Results: </strong>While podocyte-specific deletion of GIT1 in mice caused no overt phenotype and only mildly aggravated foot process effacement after injury, combined deletion of GIT1 and GIT2 resulted in severe foot process effacement, late-onset proteinuria, podocyte detachment, and focal segmental glomerulosclerosis in adulthood. In cultured podocytes, GIT2 knockdown or GIT1/GIT2 double knockdown, but not GIT1 knockdown alone, led to increased motility and accelerated focal adhesion turnover. Notably, motility of double knockdown podocytes lacked directionality and was accompanied by a significant reduction of Cdc42 activity and impaired nuclear translocation of Yes-associated protein (YAP). Mechanistically, the loss of Cdc42 activity was linked to enhanced degradation of the Cdc42-activating protein ARHGEF7, which was rescued by knockdown of the E3 ubiquitin ligase Cbl proto-oncogene B (CBL-b). Furthermore, in double knockdown podocytes, ARHGEF7 was not properly localized in focal adhesions, which was rescued by re-expressing either GIT1 or GIT2.</p><p><strong>Conclusions: </strong>Our findings demonstrate that GIT1 and GIT2 cooperatively maintain the ARHGEF7-Cdc42 signaling axis, highlighting a previously unrecognized mechanism regulating Rho GTPase activity and cytoskeletal organization in podocytes.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075190","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":"Tubular Rev-erbα deficiency aggravates kidney fibrosis via transcription factor NFIL3-driven lipid accumulation.","authors":"Xiao-Lan Wang, Jia Cheng, Yuting Zhu, Huiling Xiang, Qian Yuan, Xianfang Meng, Chun Zhang","doi":"10.1016/j.kint.2026.08.027","DOIUrl":"https://doi.org/10.1016/j.kint.2026.08.027","url":null,"abstract":"<p><strong>Introduction: </strong>Kidney metabolism and physiology exhibit circadian oscillations, which are governed by the internal circadian clock. Intracellular lipid accumulation is known to play a critical role in the pathogenesis of kidney fibrosis. However, whether and how circadian disruption accelerates the progression of kidney fibrosis remains poorly understood.</p><p><strong>Methods: </strong>To investigate the effects of circadian disruption on the kidney, a mouse model simulating shift work conditions was utilized. To further elucidate the role of circadian disruption in the pathogenesis and progression of kidney fibrosis, we generated a conditional knockout mouse model (KSP^Nr1d1^KO) with specific deletion of molecular clock Rev-erbα in kidney tubular epithelial cells. Using both KSP^{Nr1d1 KO} and control mice, we subsequently established two distinct models of kidney fibrosis.</p><p><strong>Results: </strong>In this study, we observed that circadian disruption perturbs fatty acid metabolism in the renal cortex. Rev-erbα was downregulated in two mouse models of kidney fibrosis: unilateral ureteral obstruction (UUO) and folic acid nephropathy. Tubular Rev-erbα deficiency exacerbated kidney fibrosis in both UUOand unilateral kidney ischemia-reperfusion injury- induced fibrosis models, whereas administration of the Rev-erbα agonist SR9009 attenuated fibrosis in mice. Further mechanistic studies revealed that Rev-erbα deficiency disrupted fatty acid metabolism in the kidney cortex, leading to enhanced lipid accumulation through direct transcriptional repression of Nfil3.</p><p><strong>Conclusions: </strong>Our findings demonstrate that Rev-erbα protects against kidney fibrosis by suppressing NFIL3-mediated lipid accumulation. These results suggest a vicious cycle between circadian disruption and kidney fibrosis identifying tubular Rev-erbα as a potential therapeutic target for fibrosis-related kidney diseases.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075234","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":"Data from the French Daily-Luma cohort suggest predictors of a lumasiran response.","authors":"Vittoria Soncin, Anne Laure Sellier Leclerc, Cécile Acquaviva-Bourdain, Thomas Loppinet, Olivia Boyer, Bertrand Knebelmann, Lise Allard, Claire Dossier, Sylvie Cloarec, Thomas Stehlé, François Nobili, Marie Courbebaisse, Isabelle Vrillon, Maize Ducret, Ariane Zaloszyc, Moglie Le Quintrec, Edouard Martinez Casado, Thierry Krummel, Caroline Rousset-Rouviere, Stéphane Burtey, Amélie Ryckewaert, Thierry Frouget, Massimo Di Maio, Charlotte Samaille, Emilie Cornec-Le Gall, William Hanf, Catherine Monet-Didailler, Adeline Schendel, Arnaud Garnier, Aurélie Pons, Renaud Snanoudj, Nadia Cherni, Marc Fila, Camille Faudeux, Mathilde Mauras, Inna Mohamadou, Sandrine Lemoine, Justine Bacchetta","doi":"10.1016/j.kint.2026.08.025","DOIUrl":"https://doi.org/10.1016/j.kint.2026.08.025","url":null,"abstract":"<p><strong>Introduction: </strong>Primary Hyperoxaluria type 1 (PH1) is a rare and severe autosomal recessive disorder with genotype/phenotype correlation. The RNA interfering therapy lumasiran has revolutionized its prognosis but with heterogeneous response amongst patients. Here, we assessed a possible association between genotype and lumasiran response.</p><p><strong>Methods: </strong>In the ongoing French DAILY-LUMA cohort evaluating real-life efficacy and safety of lumasiran, we collected data at treatment initiation and at months three, six and 12 of treatment. The main outcomes were composite criteria, namely normalization and/or reduction over 30% from baseline in the urinary ratio of oxalate and creatinine (UOx/Creat) or in blood oxalate levels (POx) in patients with estimated glomerular filtration rate (eGFR) over or under 30 mL/min/1.73 m², respectively. The primary endpoint was the proportion of patients reaching this criterion at three months, and secondary endpoints were the same analysis at six and 12 months. Genotype was classified into three groups depending on the vitamin B6 response: resistance, sensitivity, uncertain response (Ile244Thr variant of alanine-glyoxylate aminotransferase).</p><p><strong>Results: </strong>In total, 76 patients (54 children) were included, at a median (inter quartile range) age at lumasiran initiation of 13 (4-33) years with 24 patients on dialysis. After three months treatment, 73 % of patients met the primary endpoint (% calculated on available data). There was no significant association between the underlying genotype and lumasiran response, albeit with a trend towards a lesser response in vitamin B6- sensitive forms. The only significant determinants found to be associated with the primary outcome were age at diagnosis and age at lumasiran initiation, the best response being observed in pediatric patients.</p><p><strong>Conclusion: </strong>Our study suggests a better response to lumasiran in children independent of the underlying genotype. In patients with pyridoxine sensitivity, we suggest continuing or initiating pyridoxine even after lumasiran initiation. After lumasiran initiation, a close follow-up and re-evaluation should be systematically performed.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075156","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":"Prevalence and significance of family history of kidney disease in the electronic health record in three United States health systems.","authors":"Andrei Bucaloiu, Aditya Surapaneni, Sneha Mehta, Richard Bradshaw, Yirui Hu, Morgan E Grams, Marc S Williams, Guilherme Del Fiol, Kensaku Kawamoto, Alexander R Chang","doi":"10.1016/j.kint.2026.08.028","DOIUrl":"10.1016/j.kint.2026.08.028","url":null,"abstract":"<p><strong>Introduction: </strong>Family history is a key predictor of chronic kidney disease (CKD) and kidney failure, yet its documentation in electronic health records (EHRs) remains poorly characterized. Here, we examined the prevalence of kidney-related family history across three large United States. health systems and assessed associations with kidney disease outcomes.</p><p><strong>Methods: </strong>We conducted a cross-sectional study of 1,130,961 adults (age 18-80) receiving primary care at Geisinger, New York University Langone Health, and University of Utah Health from 2020-2023. Family history of CKD and kidney failure was ascertained from structured EHR fields and relevant search terms in comments in the family history section. Pooled prevalence of family history CKD was calculated overall and by CKD stage, using a validated EHR-based CKD phenotype. Associations between CKD family history and personal history of CKD and kidney failure were assessed using multivariable logistic regression, with pooled estimates derived via random-effects meta-analysis.</p><p><strong>Results: </strong>At least one family history field was recorded in 87.2% of individuals, with lower reporting of CKD family history (5.4%), compared to family history of diabetes (39.1%) or hypertension (35.3%). Prevalence of CKD family history was generally higher with advancing CKD stage, ranging from 6.6% for stage 2 CKD, to 10.3% for stage 3B CKD, and 17.7% for stage 5 CKD. Men and individuals under 40 years had lower family history of CKD reporting. Family history of CKD was significantly associated with CKD (pooled odds ratio 1.39, 95% confidence interval: 1.24, 1.57) and kidney failure (pooled odds ratio 3.15, 95% confidence interval: 1.92, 5.22) across cohorts, independent of demographic and clinical factors.</p><p><strong>Conclusions: </strong>CKD family history is underreported relative to other cardiometabolic conditions and positively associated with CKD and kidney failure. Improving systematic recording of CKD family history may improve early identification of high-risk individuals and inform precision medicine approaches to CKD prevention and care.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075199","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":"Impact of fluconazole in vasopressin 2 receptor-related congenital arginine vasopressin resistance.","authors":"Line A Mortensen, Claus Bistrup, Søren Rittig, Jens Michael Hertz, Kai M Schmidt-Ott, Enno Klussman, Christian Hinze, Boye L Jensen, Gitte R Hinrichs","doi":"10.1016/j.kint.2026.08.024","DOIUrl":"10.1016/j.kint.2026.08.024","url":null,"abstract":"<p><strong>Introduction: </strong>Arginine vasopressin resistance (AVP-R), previously called nephrogenic diabetes insipidus, is a rare inherited disorder characterized by excessive urine output (often over 10 l/d) and a risk of life-threatening dehydration, resulting from kidney collecting duct insensitivity to arginine vasopressin. Currently, no curative treatment exists. Preclinical studies suggest that repurposing the antifungal fluconazole enhances AQP2-mediated water transport. Here, we present results from a clinical intervention study evaluating the effect of fluconazole on 24-hour urine output and urine concentrating ability in patients with congenital AVP-R caused by a pathogenic variant in the AVPR2 gene encoding the receptor of AVP.</p><p><strong>Methods: </strong>We performed an open-label, nonrandomized intervention in five adult men with AVPR2-related AVP-R. Participants received oral fluconazole 400 mg daily for 14 days, with baseline and follow-up assessments including a water deprivation test. The primary endpoints were 24-hour urine output and urinary concentrating ability. Secondary endpoints included urinary and plasma osmolality, surrogate copeptin secretion, electrolytes, and micturition frequency. Safety and treatment adherence were evaluated weekly.</p><p><strong>Results: </strong>Median fluconazole concentration after treatment was 13.7 μg/ml (range, 12.1-24.4 μg/ml) in plasma and 28.6 μg/ml (range, 22.4-34.7 μg/ml) in urine. Median change in 24-h urine output was +0.8 L (range, -3.6 to +5.7 L) and in urine osmolality -3 mOsm/kg (range, -78 to +25 mOsm/kg), with no change in micturition frequency. During water deprivation, body weight decreased by -2.0 to -2.8 kg at baseline vs. -2.1 to -3.1 kg after treatment, urine osmolality changed by -91 to +222 mOsm/kg vs. -12 to +193 mOsm/kg, and plasma copeptin increased by 4.8 to 16.8 pmol/l vs. 4.2 to 12.9 pmol/l.</p><p><strong>Conclusions: </strong>Fluconazole treatment did not reduce urine output or improve urine concentrating ability in adult patients with congenital AVP-R.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039716","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 osteogenic regulator THOC5-dependent post-transcriptional control maintains vascular smooth muscle cell homeostasis against chronic kidney disease-related vascular calcification.","authors":"Anying Cheng, Yuyao Wang, Yu Liu, Xue Xing, Yuanyu Li, Yishen Fu, Cuntai Zhang, Yongman Lv, Li Wang, Li Li, Fan He","doi":"10.1016/j.kint.2026.08.022","DOIUrl":"10.1016/j.kint.2026.08.022","url":null,"abstract":"<p><strong>Introduction: </strong>Osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) plays a fundamental role in chronic kidney disease (CKD)-associated vascular calcification (VC). Despite its significance, the post-transcriptional control mechanisms driving VSMC osteogenic switching remain poorly understood. Here, we sought to elucidate the THOC5-dependent post-transcriptional regulatory mechanisms that control VSMC transdifferentiation and contribute to CKD-associated VC.</p><p><strong>Methods: </strong>von Kossa staining and immunohistochemistry were used to detect calcification and THOC5 expression in arterial tissues from patients with CKD and mice. In vitro and in vivo models of VSMC calcification were used to assess the effects of THOC5. RNA immunoprecipitation sequencing (RIP-Seq), RNA fluorescence in situ hybridization (RNA-FISH), and electrophoretic mobility shift assays (EMSA) were employed to elucidate the underlying regulatory mechanisms.</p><p><strong>Results: </strong>THOC5 expression was upregulated in calcified arteries from patients with CKD and mouse models. Functionally, THOC5 deficiency exacerbated VSMC calcification, while THOC5 overexpression mitigated calcification both in vitro and in vivo. Mechanistically, THOC5 selectively associated with guanine nucleotide exchange factor (GEF) mRNAs and facilitated their nuclear export and maintained their transcript stability, thereby sustaining RhoA GTPase activity. Under procalcifying conditions, this engagement was diminished, resulting in reduced RhoA activity and decreased expression of VSMC contractile markers. Pharmacological inhibition of RhoA signaling (Y27632) reversed the protective effects of THOC5. Notably, THOC5 overexpression restored GEF mRNA transport and suppressed osteogenic transition.</p><p><strong>Conclusions: </strong>Our study identifies a THOC5-GEF-RhoA regulatory axis that post-transcriptionally governs VSMC phenotypic stability during CKD-associated VC. Endogenous THOC5 upregulation in calcified vasculature likely represents a compensatory but insufficient response, as osteogenic stress impairs the formation of functional THOC5-containing export complexes. THOC5 overexpression restores this process and attenuates VC.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030730","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":"Deletion of protein FSTL3 unravels the role of activin signaling in regulating macrophage L-arginine metabolism and kidney injury.","authors":"Fei Xing, Li Xiang, Jingru Yan, Xiaoyang Chu, Yang Wang, Yonglun Kong, Jinzhong Qin, Peiyong Jiang, Hao Sun, Hequn Zou, Hui-Yao Lan, Yu Huang, Yu Zhang, Zongwei Cai, Yin Xia","doi":"10.1016/j.kint.2026.08.023","DOIUrl":"10.1016/j.kint.2026.08.023","url":null,"abstract":"<p><strong>Introduction: </strong>Macrophages play a critical role in regulating kidney injury and repair. Arginase 1 (ARG1), a key enzyme in L-arginine metabolism, is predominantly expressed in macrophages in injured kidneys. Polyamines derived from L-arginine metabolism promote the resolution of tissue injury. Follistatin-like 3 (FSTL3) is a secreted protein that acts as an antagonist of activins. However, its role in the kidney remains unknown.</p><p><strong>Methods: </strong>To study this, serum FSTL3 levels were measured in patients with chronic kidney disease (CKD) or acute kidney injury (AKI) using ELISA. Kidney injury was induced by folic acid or cisplatin in mice. Bone marrow-derived macrophages (BMDMs) were isolated from Smad3 knock out mice. Bulk RNA-seq analysis was performed on injured kidneys and BMDMs. L-arginine metabolites were analyzed with liquid chromatography-mass spectrometry.</p><p><strong>Results: </strong>Serum FSTL3 levels were elevated in patients with CKD or AKI and were negatively correlated with estimated glomerular filtration rate and positively correlated with serum creatinine levels in CKD. Deletion of Fstl3 in mice ameliorated kidney injury and fibrosis, and this protective effect was associated with increased SMAD3 phosphorylation and ARG1 expression in macrophages. RNA-seq analysis revealed that arginine metabolism was highly enriched in the injured kidneys of Fstl3 knock out mice, as well as in BMDMs treated with activin A and IL-4. In vitro, activin A drastically synergized with the Th2 cytokines IL-4 and IL-13 to stimulate the expression of Arg1, along with Slc7a2 (also known as Cat2) and glycine amidinotransferase (Gatm), two other key genes involved in L-arginine metabolism, in macrophages, leading to enhanced L-arginine metabolism and polyamine production. Following folic acid treatment, Fstl3 knock out mice exhibited reduced tubular cell apoptosis and increased tubular cell proliferation.</p><p><strong>Conclusions: </strong>Our results uncover a previously unrecognized role for activin signaling in the regulation of L-arginine metabolism in macrophages. Fstl3 deletion activates this metabolism, thereby facilitating the resolution of kidney injury.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030677","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":"Results from the Phase 2 Explore-CKD Trial of lorundrostat, a novel aldosterone synthase inhibitor, in participants with uncontrolled hypertension, chronic kidney disease, and albuminuria.","authors":"Matthew R Weir, Sarbani Bhaduri, Keung Lee, Oscar Galvez, Laura Kooienga, Branko Kopjar, Matthew Novin, David Rodman","doi":"10.1016/j.kint.2026.08.021","DOIUrl":"10.1016/j.kint.2026.08.021","url":null,"abstract":"<p><strong>Introduction: </strong>Dysregulated aldosterone plays an important role in the pathogenesis of hypertension (HTN) and chronic kidney disease (CKD). Lorundrostat, a highly selective aldosterone synthase inhibitor, has demonstrated efficacy and safety for uncontrolled HTN (uHTN) and treatment-resistant HTN in multiple well-controlled clinical trials, although its efficacy in patients with uHTN and CKD is not fully established.</p><p><strong>Methods: </strong>This was a randomized, double-blind, placebo-controlled, crossover trial of lorundrostat (25 mg/day) added to a sodium-glucose cotransporter-2 inhibitor (SGLT2i) in adults with uHTN, CKD, and albuminuria on stable treatment with a renin-angiotensin-aldosterone system blocker. Participants were randomized to lorundrostat-placebo or placebo-lorundrostat in four-week treatment sequences with a four-week washout period. The primary end point was change in automated office systolic blood pressure (AOSBP). Other endpoints included change in urine albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR).</p><p><strong>Results: </strong>The 59 participants had a mean age of 64.6 years, mean body mass index of 33 kg/m², and 76% had type 2 diabetes. At baseline, mean AOSBP was 149±10.4 mm Hg, geometric mean UACR (spot) was 516.8±2.51 mg/g, and cystatin C-eGFR was 43±15.0 mL/min per 1.73 m². Least squares mean change in AOSBP was -1.8 mm Hg (95% Confidence Interval, -5.6, 2.1) with placebo and -9.3 mm Hg (-13.1, -5.4) with lorundrostat (placebo-adjusted, - 7.5 mm Hg (-12.3, -2.7)). Reduction in geometric mean of UACR was 30.5% (-41.0, -18.2) placebo-adjusted, 25.6% (-37.7, -11.2). eGFR decreased from 42.9±15.2 to 40.1±16.0 mL/min per 1.73 m² with lorundrostat and from 42.9±15.1 to 42.1±15.8 mL/min per 1.73 m² with placebo. Three participants discontinued treatment due to adverse events (hyperkalemia/CKD worsening, acute kidney injury, and retinal detachment).</p><p><strong>Conclusions: </strong>Lorundrostat added to SGLT2i reduced AOSBP and albuminuria in patients with uHTN and CKD and was associated with an acceptable safety profile. The observed reduction in albuminuria may suggest a potential cardiorenal benefit. However, longer-term studies are needed to determine whether these findings translate into durable kidney or cardiovascular outcomes.</p><p><strong>Trial registration: </strong>Registered at ClinicalTrials.gov with study number NCT06150924.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030669","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}