J Am Soc Nephrol
· 2026 May · PMID 41563815
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Aging is unavoidable and driven, at least in part, by the biologic process termed senescence. Senescence is characterized by cell cycle arrest incurred by one or more stressors wherein there is cellular upregulation of c...Aging is unavoidable and driven, at least in part, by the biologic process termed senescence. Senescence is characterized by cell cycle arrest incurred by one or more stressors wherein there is cellular upregulation of cyclin-dependent kinase inhibitors, p16 Ink4a and/or p21 Cip1 . Senescent cells are metabolically active and resistant to apoptosis, have increased β -galactosidase activity, and express a senescence-associated secretory phenotype (SASP). The SASP produces an array of inflammatory, cytotoxic, fibrotic, and vasoactive factors. Senescence is a diffusible process as, largely through the SASP, a focus of senescent cells can recruit adjacent cells and cells in distant organs, thereby expanding its scope way beyond its original focus. Senescence predisposes not only to chronic diseases (including CKD) but also acute processes (including AKI). This review provides evidence that age increases the risk of human AKI and summarizes clinical factors that predispose older individuals to AKI. It provides an overview of the biology of senescence, and it discusses the role of intrarenal senescent cells in the pathogenesis of AKI, the significance of the extrarenal milieu and distant organs in predisposing to AKI with age, heme as a prosenescent species, and the role of senescence in the AKI to CKD transition. The risk for AKI with aging, in large part, reflects the fact that virtually all processes implicated in AKI, irrespective of age, occur as the kidney ages. Processes discussed include senescent cells, vascular responses, diabetes, impaired NAD + content, sirtuin expression, mitochondrial dysfunction, impaired autophagy, epigenetic changes, telomere shortening, impaired nephroprotectant expression, inflammaging, and immunosenescence. The review concludes by discussing the basis for senolytics (agents that kill senescent cells), senomorphics (agents that block SASP factors), and other aspects of senotherapies.
Lidgard B, Hoofnagle AN, Zelnick LR
… +7 more, de Boer IH, Jensen P, Fretts AM, Siscovick DS, Umans JG, Bansal N, Lemaitre RN
J Am Soc Nephrol
· 2026 Jun · PMID 41563809
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KEY POINTS: Sphingolipids with long fatty acids (16-18 carbons) were associated with all-cause and cardiovascular death in patients treated with hemodialysis. Sphingolipids with very-long fatty acids (20+ carbons) were a...KEY POINTS: Sphingolipids with long fatty acids (16-18 carbons) were associated with all-cause and cardiovascular death in patients treated with hemodialysis. Sphingolipids with very-long fatty acids (20+ carbons) were associated with lower risk of all-cause and cardiovascular death in dialysis patients. BACKGROUND: Patients with kidney failure on hemodialysis are at a higher risk for death, especially cardiovascular death. Statins (which improve outcomes in general populations) do not improve outcomes in dialysis patients. Sphingolipids are mechanistically associated with cardiovascular disease and may represent novel, modifiable risk factors for death in patients with kidney failure. We aimed to examine the associations of sphingolipids with death specifically in dialysis patients. METHODS: Using data from the Hemodialysis (HEMO) Study (a multicenter factorial trial of dose and flux), we measured 16 sphingolipids (ceramides-16:0, 18:0, 20:0, 22:0, 24:0, and 24:1; hexosylceramides-16:0, 22:0, and 24:0; lactosylceramide-16:0; and sphingomyelins 14:0, 16:0, 18:0, 20:0, 22:0, and 24:0) at baseline only in 927 participants with available stored serum using targeted liquid chromatography-tandem mass spectrometry. The primary outcome was all-cause death, with physician-adjudicated cause (cardiovascular versus noncardiovascular) as a secondary outcome. We examined the associations of sphingolipids with death using Cox regressions, controlling the false discovery rate <5%. RESULTS: Among 927 participants, the mean (SD) age was 57 (14) years; median (interquartile range) dialysis vintage was 1.9 (0.8-4.1) years. Over a median (interquartile range) follow-up of 2.4 (1.4-4.0) years, there were 376 deaths. Nine of 16 sphingolipids were significantly associated with death, including ceramide-16:0 (adjusted hazard ratio [aHR] 2.13 per two-fold higher concentration, 95% confidence interval, 1.48 to 3.06), and ceramide-22:0 (aHR per two-fold higher 0.59, 95% confidence interval, 0.44 to 0.79), with similar direction of associations for sphingomyelins. Twelve of 16 sphingolipids were associated with cardiovascular death, for example, ceramide-16:0 (aHR per two-fold higher 3.43, 95% confidence interval, 2.05 to 5.74). No sphingolipid was significantly associated with noncardiovascular death. CONCLUSIONS: In a dedicated study of patients with kidney failure on hemodialysis, sphingolipids with long-chain fatty acids were strongly associated with greater risk of death, especially cardiovascular death.
Li C, Liu Y, Zhao H
… +9 more, Xi Y, Liu C, Luo S, Jiang N, Yang M, Han Y, Chen W, Li L, Sun L
J Am Soc Nephrol
· 2026 May · PMID 41563806
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KEY POINTS: Phosphofurin acidic cluster sorting protein 2 (PACS-2) expression was lower in fibrotic kidney tubule, and proximal tubule-specific deficiency accelerated the progression of CKD. PACS-2 deficiency exacerbated...KEY POINTS: Phosphofurin acidic cluster sorting protein 2 (PACS-2) expression was lower in fibrotic kidney tubule, and proximal tubule-specific deficiency accelerated the progression of CKD. PACS-2 deficiency exacerbated G2/M cell cycle arrest in proximal tubular cells to promote kidney fibrosis. PACS-2 interacted with cyclin-dependent kinase-like 1 and modulated its kinase activity, thereby regulating cell cycle progression. BACKGROUND: Kidney fibrosis is the final common pathway of CKD. Proximal tubular epithelial cells (PTECs) arrested in G2/M phase of the cell cycle play a pivotal role in kidney fibrosis. Phosphofurin acidic cluster sorting protein 2 (PACS-2) is a multifunctional protein involved in various cellular activities including cell cycle regulation, yet its role in kidney fibrosis remains unclear. METHODS: PTEC-specific Pacs-2 knockout mice were generated by using LoxP-Cre recombination system and subjected to unilateral ureteral obstruction (UUO) and aristolochic acid to induce kidney fibrosis. Cultured human and mouse tubular epithelial cells were treated with TGF- β 1 to analyze the underlying cellular mechanisms. Coimmunoprecipitation coupled with mass spectrometry, molecular cloning, and genetic manipulation were used to investigate PACS-2 interactions and specific binding domains. RESULTS: PACS-2 expression was significantly lower in the cortex of fibrotic kidney from UUO mouse. PACS-2 deficiency in PTECs exacerbated G2/M cell cycle arrest and kidney fibrosis in murine UUO and aristolochic acid nephropathy models, two independent models for CKD. In vitro , overexpression of PACS-2 alleviated TGF- β 1-induced fibrogenic responses in PTECs through inhibiting cell cycle arrest at G2/M phase. By coimmunoprecipitation coupled with mass spectrometry, we identified cyclin-dependent kinase-like 1 (CDKL1) as the key molecule linking PACS-2 to cell cycle progression in PTECs. Knockdown of CDKL1 partially reversed the antifibrotic effects of PACS-2 by promoting G2/M cell cycle arrest in TGF- β 1-stimulated HK-2 cells. Mechanistically, we demonstrated that PACS-2 interacted with kinase domain of CDKL1 and modulated its kinase activity, thereby regulating cell cycle, rather than affecting its subcellular translocation or protein expression. CONCLUSIONS: Our study demonstrates that renal tubular PACS-2 alleviated G2/M cell cycle arrest and kidney fibrosis by interacting with CDKL1 and modulating its kinase activity.
Marques E, Alves Teixeira M, Ramauge Parra C
… +8 more, Isnard P, Kelly-Aubert M, Nguyen C, Lake J, Nemazanyy I, Rugarli EI, Terzi F, Gallazzini M
J Am Soc Nephrol
· 2026 Jun · PMID 41563805
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KEY POINTS: Lipocalin-2 inhibited clustered mitochondrial homolog (CLUH) activity and caused mitochondrial dysfunction. Loss of CLUH in kidneys triggered metabolic reprogramming and impaired mitochondrial structure. CLUH...KEY POINTS: Lipocalin-2 inhibited clustered mitochondrial homolog (CLUH) activity and caused mitochondrial dysfunction. Loss of CLUH in kidneys triggered metabolic reprogramming and impaired mitochondrial structure. CLUH expression decreased with kidney injury and correlated with kidney function decline in patients. BACKGROUND: Lipocalin-2 (LCN2) is a secreted protein involved in transporting hydrophobic molecules, regulating antibacterial responses and iron homeostasis. LCN2 expression increases after kidney damage and participates in CKD onset. We previously identified LCN2 as a regulator of mitochondrial dysfunction in renal tubular cells. This study aims to better understand LCN2's role in mitochondrial dysfunction and kidney pathology. METHODS: LCN2 interactome was studied using mass spectrometry. The impact of LCN2 on clustered mitochondrial homolog (CLUH) activity was explored by immunofluorescence, Western blot, quantitative PCR, and RNA-immunoprecipitation. The role of CLUH on mitochondrial function in kidney was evaluated by RNAseq, metabolomics, electron microscopy, and immunochemistry using transgenic mice. RESULTS: We characterized LCN2 interactome and identified CLUH in a multiprotein complex with LCN2. CLUH regulates mitochondrial homeostasis by binding mRNAs of nuclear-encoded mitochondrial proteins and promoting their translation. We demonstrated that LCN2 inhibited CLUH activity, leading to perinuclear mitochondrial clustering. We showed that CLUH was expressed in renal tubular cells and that its expression and activity decreased, while LCN2 expression increased after kidney injury leading to CKD. In human CKD patients, CLUH expression was inversely correlated with kidney lesions and kidney failure. CLUH genetic deletion in kidney nephron induced mitochondrial dysfunction and a subsequent interstitial fibrosis and kidney loss of function. CONCLUSIONS: This study shows that LCN2 forms a complex with CLUH and inhibits its activity, leading to perinuclear mitochondrial clustering. CLUH loss of function in renal tubular cells is associated with mitochondrial dysfunction and fibrosis, and in humans, CLUH expression inversely correlates with kidney lesions and loss of function.
KEY POINTS: Dual inactivation of Glis3 and Pkd1 exacerbated polycystic kidney disease compared with Pkd1 inactivation alone in mouse models of autosomal dominant polycystic kidney disease. RNA-Seq and ATAC-Seq suggested...KEY POINTS: Dual inactivation of Glis3 and Pkd1 exacerbated polycystic kidney disease compared with Pkd1 inactivation alone in mouse models of autosomal dominant polycystic kidney disease. RNA-Seq and ATAC-Seq suggested Glis3 inactivation resulted in dysregulated fatty acid metabolism and alteration of circadian regulation. Glis3 was involved in a transcriptional network consisting of the transcription factors HNF1 homeobox B, hepatic nuclear factor 4, alpha, and D site albumin promoter binding protein. BACKGROUND: Autosomal dominant polycystic kidney disease is caused by mutations affecting polycystin-1 or polycystin-2. The existence of a cilia-dependent cyst activation pathway has been identified by showing that structurally intact primary cilia are crucial for rapid cyst growth following loss of polycystins. We previously used translating ribosome affinity purification RNA-Seq on precystic mouse kidneys to determine a translatome that meets the criteria for cilia-dependent cyst activation. From this, we identified Glis2 as an early effector of polycystin signaling and a potential target for therapy. Here, we investigate the role of Glis3 which, while not transcriptionally altered in autosomal dominant polycystic kidney disease models, encodes a cilia-localized transcription factor belonging to the same gene family as Glis2 . METHODS: We used live cell imaging along with gene and protein expression studies to determine the relationships between Glis3, Glis2, and polycystin-1 expression. We used Glis3 conditional knockout mice to investigate the in vivo genetic interaction between Glis3 and Pkd1 . We used gene expression and chromatin accessibility analyses by RNA-Seq and ATAC-Seq, respectively, on an allelic series of Glis3 and Pkd1 inactivation models to explore the genetic relationships between the two genes. RESULTS: The ciliary localization of Glis3 was not affected by Pkd1 mutation status. Kidney selective inactivation of Glis3 by itself did not affect kidney structure or function, but dual inactivation of Glis3 and Pkd1 significantly worsened polycystic kidney disease. Integration of transcriptomic profiling and chromatin accessibility assays suggested that kidney tubule-specific Glis3 inactivation resulted in dysregulated fatty acid metabolism and alteration of circadian regulation. CONCLUSIONS: Glis3 is a primary cilium localized transcription factor that genetically interacts with Pkd1 and modifies kidney epithelial cell metabolism and circadian function.
J Am Soc Nephrol
· 2026 Mar · PMID 41563801
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Mechanical circulatory support is used to augment circulatory flow in cardiogenic shock and end-stage heart failure. Support can last from hours for temporary mechanical circulatory support to years for durable mechanica...Mechanical circulatory support is used to augment circulatory flow in cardiogenic shock and end-stage heart failure. Support can last from hours for temporary mechanical circulatory support to years for durable mechanical circulatory support. The physiologic relationship of heart and kidney function and the epidemic of cardio-kidney-metabolic disease lead to frequent use of simultaneous mechanical circulatory support and extracorporeal KRT (dialysis). The need for dialysis can range from short periods of AKI in cardiogenic shock to long-term dialysis for individuals who receive left ventricular assist devices (LVADs) for destination therapy in advanced heart failure and progress to CKD G5 with replacement therapy. Changes in technology, clinical evidence, and organ transplantation have led to major changes in mechanical circulatory support use. With temporary mechanical circulatory support, devices and clinical situations vary widely, with intra-aortic balloon pumps, microaxial flow pumps, and venoarterial extracorporeal membrane oxygenation providing different levels of circulatory support. Considerations for dialysis, whether for AKI or CKD G5, are discussed. In durable mechanical circulatory support, LVADs are now used primarily for permanent therapy, and most LVAD recipients survive for more than 5 years, time in which kidney dysfunction can develop or progress. Outpatient dialysis with LVADs is performed for both AKI and for CKD G5, with in-center intermittent hemodialysis, peritoneal dialysis, or home hemodialysis. This article discusses considerations specific to dialysis in temporary and durable circulatory support, including the challenging aspects of volume management and complication risks. Concurrent mechanical circulatory support and dialysis present diverse clinical challenges in patients with complex medical needs. Meeting this challenge requires close cooperation and shared decision making incorporating cardiologists, nephrologists, other medical professionals, patients, and their caregivers.
Zhang Y, Zou H, Ni X
… +15 more, Tie F, Xu B, Kang Y, Xiang W, Li Y, Jia C, Tan Y, Liu L, Lv J, Xiao J, Xu G, Yu L, Zhao M, Zhu L, Zhang H
J Am Soc Nephrol
· 2026 Jun · PMID 41563799
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KEY POINTS: CFHR3*B haplotype was a susceptibility variant for IgA nephropathy diagnosis by enhancing complement activation. The rs446868A variant in CFHR3*B elevated CFHR3 transcription and was associated with higher ci...KEY POINTS: CFHR3*B haplotype was a susceptibility variant for IgA nephropathy diagnosis by enhancing complement activation. The rs446868A variant in CFHR3*B elevated CFHR3 transcription and was associated with higher circulating FHR3 levels in patients with IgA nephropathy. FHR3241Ser variant enhanced C3b binding and complement activation, accelerating IgA deposition-induced complement activation in IgA nephropathy. BACKGROUND: Complement activation is involved in IgA nephropathy. We previously identified that genetic deletion of CFHR3 and CFHR1 confers protection against IgA nephropathy by modulating complement activation. In addition, the CFHR3*B haplotype (rs385390C/rs446868A/rs138675433T/rs149352569T) has been linked to elevated CFHR3 transcription and higher risk of atypical hemolytic uremic syndrome. METHODS: We evaluated the association between the CFHR3*B haplotype and IgA nephropathy susceptibility by using genetic analysis of 1108 patients with IgA nephropathy and 630 healthy controls. Luciferase activity assays were performed to assess the transcriptional activity of CFHR3*B haplotype. The coding variant rs138675433 (FHR3 241Pro versus FHR3 241Ser ) was assessed using recombinant proteins to determine its effect on complement regulation. RESULTS: The CFHR3*B haplotype and CFHR3*BB genotype were significantly enriched in patients with IgA nephropathy. The CFHR3*BB genotype correlated with lower circulating C3 levels and greater glomerular C3 deposition. Luciferase activity assays demonstrated enhanced transcription activity conferred by the CFHR3*B haplotype, with rs446868 identified as the functional regulatory variant. Patients carrying the CFHR3*BB genotype exhibited elevated circulating FHR3 levels. FHR3 241Ser exhibited significantly enhanced C3b-binding capacity and factor H deregulation activity, promoting accelerated C3 convertase formation and increased hemolysis. Furthermore, FHR3 241Ser augmented IgA deposition-induced complement activation on cultured mesangial cells in a dose-dependent manner. CONCLUSIONS: Our results identified CFHR3*B haplotype as a susceptibility variant for IgA nephropathy diagnosis by accelerating complement activation, through rs446868A enhancing transcription activity and rs138675433T augmenting FHR3 function.
Liu Y, Chen P, Chen G
… +13 more, Hong J, Zhou Y, Zheng K, Ai S, Gao Z, Xia P, Cui H, Wang R, Shi X, Li X, Li X, Zhang L, Qin Y
J Am Soc Nephrol
· 2026 May · PMID 41563797
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KEY POINTS: Based on the yeast surface display system, we identified three new antigen epitopes of CTLD4, CTLD5, and CTLD6 of phospholipase A2 receptor in membranous nephropathy. In the cohort, 82% of patients showed epi...KEY POINTS: Based on the yeast surface display system, we identified three new antigen epitopes of CTLD4, CTLD5, and CTLD6 of phospholipase A2 receptor in membranous nephropathy. In the cohort, 82% of patients showed epitopes beyond Ricin and 56% higher risk for nephrotic syndrome per one more epitope (odds ratio, 1.56; 95% confidence interval, 1.28 to 1.91). Each additional epitope was associated with 15% lower likelihood in clinical remission in this membranous nephropathy cohort (hazard ratio, 0.85; 95% confidence interval, 0.75 to 0.96). BACKGROUND: The M-type phospholipase A2 receptor (PLA2R) is the main target antigen of idiopathic membranous nephropathy. Four autoantibody-targeted PLA2R epitope domains, including Ricin, CTLD1, CTLD7, and CTLD8, have been identified. Nevertheless, whether the epitope profile is involved in the progression of PLA2R-associated membranous nephropathy remains controversial. Conventional epitope detection techniques have limitations, and new methods are needed. METHODS: We constructed a yeast surface-displayed PLA2R antigen library by randomly fragmenting the full-length PLA2R gene and expressing them on the yeast surfaces. Fluorescence-activated cell sorting was performed with sera from PLA2R-related membranous nephropathy patients. Antigenic epitopes were identified through sequencing and clustering. To analyze large-scale samples in batches, we used representative monoclonal yeasts of each structural domain, obtained through the sorting procedure for flow analysis. Clinical and laboratory data were collected at baseline and follow-up. Associations between epitope numbers and disease conditions and prognosis were analyzed. RESULTS: The capacity, diversity, and screening specificity of the PLA2R yeast surface display library were validated. Beyond the reported epitopes, CTLD4, CTLD5, and CTLD6 were newly identified as antigenic targets. In our cohort of 389 idiopathic membranous nephropathy patients, 320 (82%) patients showed epitopes beyond the Ricin domain. The positive rates of CTLD1, CTLD5, and CTLD7 were 53%, 45%, and 54%, respectively, while the detection rates of CTLD6, CTLD8, and CTLD4 were lower at 9%, 8%, and 7%, respectively. The multivariable model demonstrated a 56% higher risk for nephrotic syndrome per epitope increment (odds ratio, 1.56; 95% confidence interval, 1.28 to 1.91) after adjustment for gender, age, disease duration, serum creatinine, and anti-PLA2R titer. Multivariable Cox regression demonstrated that each additional epitope was associated with a 15% lower likelihood in clinical remission (hazard ratio, 0.85; 95% confidence interval, 0.75 to 0.96), with subsequent mediation analysis revealing anti-PLA2R titer accounted for 12% of this effect. CONCLUSIONS: Based on the PLA2R yeast surface display system, we identified three new antigen epitopes of PLA2R in membranous nephropathy. The epitope profiles of PLA2R were associated with disease severity and prognosis of membranous nephropathy.