Arteriovenous (AV) fistulas, the preferred vascular access for hemodialysis, fail to mature in up to 60% of patients with kidney failure. This high failure rate is often attributed to adverse hemodynamic conditions, yet...Arteriovenous (AV) fistulas, the preferred vascular access for hemodialysis, fail to mature in up to 60% of patients with kidney failure. This high failure rate is often attributed to adverse hemodynamic conditions, yet the exact mechanisms remain poorly understood. This review explores the application of computational fluid dynamics and machine learning to elucidate these mechanisms and predict clinical outcomes. Computational fluid dynamic models have been instrumental in characterizing the complex interplay between AV fistula geometry, such as anastomotic angle and curvature, and hemodynamic parameters, such as wall shear stress and oscillatory shear index. These studies consistently link disturbed flow patterns, including low wall shear stress and high oscillatory shear index, to regions prone to neointimal hyperplasia and stenosis. Concurrently, machine learning models have demonstrated significant promise in predicting AV fistula maturation, stenosis, and failure by leveraging diverse data sources, including clinical characteristics, ultrasound imaging, and acoustic bruit analysis. While powerful, the clinical utility of these computational models is often limited by small, single-center datasets, a lack of external validation, and simplifying assumptions that may not capture true physiological complexity. Future progress depends on integrating these complementary approaches, using larger and more diverse datasets, and validating models prospectively to create generalizable tools that can guide surgical planning and improve AV fistula maturation rates.
KEY POINTS: Use of glucocorticoids, opioids, and loop diuretics raised cystatin C independent of GFR. Except for glucocorticoids, cystatin C increases were small and likely clinically nonmeaningful. Consequently, the und...KEY POINTS: Use of glucocorticoids, opioids, and loop diuretics raised cystatin C independent of GFR. Except for glucocorticoids, cystatin C increases were small and likely clinically nonmeaningful. Consequently, the underestimation of eGFR cys was larger in medication users; combined eGFR cr-cys was most accurate. BACKGROUND: Serum cystatin C is influenced by factors beyond GFR, and several medications have been hypothesized to alter its generation. Whether reported associations reflect effects on cystatin C independent of measured GFR (mGFR) or confounding by illness remains unclear. METHODS: We studied 5595 adults who underwent outpatient cystatin C (and creatinine) testing with mGFR determination using iohexol clearance in Stockholm health care. Associations between eight candidate medication classes and cystatin C were assessed using both interindividual and intraindividual analyses, sequentially adjusting for mGFR, clinical variables, and ongoing medications. We further evaluated the effect of these medications on cystatin C-based eGFR (eGFR cys ) bias compared with serum creatinine-based (eGFR cr ) and combined (eGFR cr-cys ) equations. RESULTS: After adjustment for mGFR and confounders, the use of systemic glucocorticoids, opioids, and loop diuretics was associated with higher cystatin C. The magnitude of increase was potentially clinically meaningful for glucocorticoid use, particularly for greater estimated daily dose categories, whereas the smaller increases observed with opioid and loop diuretic use likely reflect clinically nonmeaningful effects. No associations were observed for use of allopurinol, immunosuppressants, thyroid hormone analogues, or antipsychotics or for paracetamol after adjustment for concomitant medications. eGFR cys underestimated mGFR more in users than in nonusers, while eGFR cr overestimated mGFR similarly in users and nonusers. eGFR cr-cys provided the least biased GFR estimates. CONCLUSIONS: This study suggests that systemic glucocorticoids, opioids, and loop diuretics may increase cystatin C independent of mGFR. The use of eGFR cr-cys was consistently more accurate than either eGFR cr or eGFR cys alone in patients using these treatments.
KEY POINTS: Global deletion of angiopoietin-2 protected against the progression of CKD. Endothelial cell-derived angiopoietin-2 drove early inflammation by promoting endothelial activation. Tubular epithelial cell-derive...KEY POINTS: Global deletion of angiopoietin-2 protected against the progression of CKD. Endothelial cell-derived angiopoietin-2 drove early inflammation by promoting endothelial activation. Tubular epithelial cell-derived angiopoietin-2 contributed to functional decline and kidney fibrosis in advanced CKD. BACKGROUND: CKD is driven by inflammation, vascular dysfunction, and fibrosis, with emerging evidence implicating angiopoietin-2 as a key mediator. While angiopoietin-2 is produced by endothelial cells and upregulated in injured tubular epithelial cells (TECs), the distinct contributions of endothelial cell-derived and TEC-derived angiopoietin-2 remain unclear. This study defines the cell type-specific roles of angiopoietin-2 in CKD pathogenesis. METHODS: We examined kidney transcriptomes and outcomes from the Taipei Renal Transcriptomics and Outcomes Investigation cohort, with fibrosis assessed by histology and RNA sequencing. Global, endothelial cell-specific, and TEC-specific angiopoietin-2 knockout mice were subjected to experimental CKD. Kidney injury, inflammation, vascular changes, and fibrosis were evaluated using histologic, molecular, and imaging analyses. RESULTS: In patients with CKD, elevated kidney ANGPT2 mRNA was associated with lower estimated glomerular filtration rate, greater kidney fibrosis, and adverse kidney outcomes. Global deletion of angiopoietin-2 in mice preserved kidney function and reduced inflammation, vascular rarefaction, and fibrosis during CKD progression induced by an adenine diet. Transcriptomic profiling revealed suppression of proinflammatory and profibrotic pathways and enhancement of peroxisomal lipid metabolism. Endothelial cell-specific deletion of angiopoietin-2 attenuated early inflammatory signaling and endothelial activation but failed to prevent late-stage vascular rarefaction and fibrosis. By contrast, TEC-specific deletion preserved kidney function and reduced fibrotic and vascular injury in late-stage CKD, without impacting early inflammation and endothelial activation. Mechanistically, angiopoietin-2 promoted macrophage recruitment and matrix deposition through cell-specific pathways, without directly altering metabolism of TECs. CONCLUSIONS: This study identifies angiopoietin-2's contribution to CKD pathogenesis through distinct roles of endothelial and tubular epithelial sources. Endothelial deletion mainly reduced early inflammation, while tubular epithelial deletion limited progressive injury and advanced fibrosis.
Davis JW, Layton JB, Sahrmann JM
… +4 more, Nickel KB, Dharnidharka VR, Weber DJ, Butler AM
J Am Soc Nephrol
· 2026 Apr · PMID 41973506
·
Full text
KEY POINTS: In patients with kidney failure, enhanced influenza vaccine formulations may provide modestly increased protection versus standard-dose vaccines. This cohort study compared the risk of influenza-like illness,...KEY POINTS: In patients with kidney failure, enhanced influenza vaccine formulations may provide modestly increased protection versus standard-dose vaccines. This cohort study compared the risk of influenza-like illness, influenza, influenza-related hospitalization, severe influenza, and all-cause mortality by vaccine formulation. Findings support new Centers for Disease Control and Prevention guidelines recommending enhanced influenza vaccine formulations in adults ≥65 years, regardless of kidney failure. BACKGROUND: Influenza vaccination is recommended to prevent influenza in patients with kidney failure. It remains unclear whether newer, enhanced vaccine formulations are more effective than standard-dose, egg-based, inactivated influenza vaccine (standard-dose vaccine) in patients undergoing maintenance hemodialysis. We sought to compare the effectiveness of five influenza vaccine formulations among patients undergoing hemodialysis. METHODS: Using the United States Renal Data System database, we performed an active comparator cohort study among adults ≥65 years with kidney failure undergoing hemodialysis (2011/2012-2019/2020 influenza seasons) who received a standard-dose, high-dose, cell culture-based, adjuvanted, or recombinant influenza vaccine within a given season. We compared the risk of influenza-like illness, influenza, influenza-related hospitalization, severe influenza, and all-cause mortality during the influenza season by vaccine formulation. Season-specific risk differences and relative vaccine effectiveness (rVE) were estimated using propensity score-weighted Kaplan-Meier functions, accounting for the competing risk of death (for nonmortality outcomes). We combined the season-specific estimates via a random effects meta-analysis. RESULTS: 578,232 influenza patient-seasons included standard-dose vaccine ( n =372,907), high-dose vaccine ( n =192,880), cell culture-based vaccine ( n =8177), adjuvanted vaccine ( n =3308), or recombinant vaccine ( n =960). Season-specific and meta-analytic estimates were consistent with a modest protective effect of high-dose vaccine versus standard-dose vaccine for influenza (meta-analytic rVE 5.1%; 95% confidence interval [CI], -0.7% to 10.5%), influenza-related hospitalization (meta-analytic rVE 5.5%; CI, -1.8% to 12.3%), and severe influenza (meta-analytic rVE 13.7%; CI, -9.7% to 32.1%), but not influenza-like illness or mortality. Patterns were similar for cell culture-based vaccine versus standard-dose vaccine ( e.g ., meta-analytic rVE for influenza, 18.3%; CI, 2.2% to 31.7%). Estimates for adjuvanted or recombinant versus standard-dose vaccines were imprecise. Quantitative bias analyses did not indicate residual confounding, although some estimates were imprecise. CONCLUSIONS: Among older adults undergoing hemodialysis, high-dose vaccine and cell culture-based vaccine provided modestly increased protection versus standard-dose vaccine.
Li C, Yang L, Ku J
… +16 more, Boor P, Zu J, Han C, Kuang M, Fei Y, Liu F, Long H, Li Q, Chang L, Yang H, Chu X, Aghakishi H, Klinkhammer BM, Gudermann T, Mammadova-Bach E, Anders HJ
KEY POINTS: Cholesterol crystal embolism causes arterial thrombosis, ischemic necrosis, and organ dysfunction. Genetic depletion of cyclophilin D reduced cholesterol crystal embolism-induced thromboinflammation and prote...KEY POINTS: Cholesterol crystal embolism causes arterial thrombosis, ischemic necrosis, and organ dysfunction. Genetic depletion of cyclophilin D reduced cholesterol crystal embolism-induced thromboinflammation and protected organ function. Pharmacological inhibition of cyclophilin D and transmembrane protein 16F limited cholesterol crystal embolism-induced thrombosis and improved kidney function. BACKGROUND: Cholesterol crystal embolism is a severe consequence of advanced atherosclerosis, where intra-arterial cholesterol crystal can trigger organ injury and failure. Cyclophilin D (CypD), a key regulator of the mitochondrial permeability transition pore, promotes procoagulant platelet formation and necrosis. We hypothesized that CypD-dependent procoagulant platelet formation enhances cholesterol crystal embolism-induced thromboinflammatory responses and kidney injury. METHODS: We used CypD-deficient mice and pharmacologic inhibitors (cyclosporine A to block CypD and niflumic acid to inhibit transmembrane protein 16F as a downstream effector of CypD) to determine the role of CypD during cholesterol crystal-induced kidney thromboinflammation and injury. RESULTS: Cholesterol crystal injection into the renal artery caused infarction, thromboinflammation, and AKI in wild-type mice, whereas CypD-deficient mice were protected. Global or platelet-specific CypD deletion preserved GFR, reduced infarct size, and attenuated tubular damage. Pharmacological inhibition of CypD with cyclosporin A conferred similar protection. Inhibition of transmembrane protein 16F-dependent phosphatidylserine exposure with niflumic acid also reduced CypD-mediated procoagulant activity and limited kidney injury. CONCLUSIONS: Our findings identified platelet CypD and downstream phosphatidylserine exposure as key mediators of cholesterol crystal-induced thromboinflammation.
Vrbacká A, Přistoupilová A, Kidd KO
… +41 more, Janoušek V, Radina M, Vylet'al P, Bitar I, Stránecký V, Steiner-Mrázová L, Trešlová H, Sovová J, Hodaňová K, Hartmannová H, Mušálková D, Svojšová K, Kmochová T, Barešová V, Bleyer H, Taylor A, Martin L, Sanchez A, Ryšavá R, Lajtmanová I, Rajnochová-Bloudíčková S, Viklický O, Papagregoriou G, Deltas C, Stavrou C, Jorge S, Lopes JA, Rodrigues M, Elhassan E, Clince M, Rowan C, Conlon P, Teltsh O, Cavalleri GL, Blumenstiel B, Toledo D, DiStefano M, DeFelice M, Živná M, Bleyer AJ, Kmoch S
KEY POINTS: Single-molecule real-time sequencing with the PacMUC1 script resolved exact MUC1 variable tandem repeat structure and full allelic variation. In 300 individuals, the protocol identified 215 distinct MUC1 tand...KEY POINTS: Single-molecule real-time sequencing with the PacMUC1 script resolved exact MUC1 variable tandem repeat structure and full allelic variation. In 300 individuals, the protocol identified 215 distinct MUC1 tandem repeat alleles with 80 repeat units and nine frameshift mutation types. Probe extension assay identified 90% of families with frameshift mutations, detection of frameshifted mucin-1 aided genetically unresolved cases. BACKGROUND: ADTKD- MUC1 is caused by frameshift mutations in the MUC1 gene, producing a frameshifted neoprotein (MUC1fs) toxic to kidney cells. The gene's variable number of tandem repeats (VNTR), with approximately 80% guanine/cytosine content, has made it largely inaccessible to standard short-read sequencing, leaving the reference sequence and natural variation poorly defined and complicating mutation detection. METHODS: Using single-molecule real-time (SMRT) sequencing, we characterized MUC1 VNTR in 300 individuals, including 279 from 143 families suspected of having ADTKD- MUC1 , assessing VNTR length, repeat structure, and frameshift mutations. Results were compared with the Clinical Laboratory Improvement Amendments-approved probe-extension assay, detecting the prevalent 59dupC mutation, and with MUC1fs immunohistochemistry, which detects the pathogenic protein independent of the underlying genomic change. RESULTS: We identified 215 unique VNTR alleles composed of 80 distinct repeat units, 46 (58%) of which were novel, and nine distinct frameshift mutations present on 52 mutated alleles. Overall, MUC1 frameshift mutations were identified in 71 of 143 families (50%) with suspected ADTKD- MUC1 , comprising 135 affected individuals (48%). The SMRT assay outperformed the probe-extension assay by identifying frameshift mutations in two families with previously inconclusive results and in eight additional families whose mutations were undetectable by the probe-extension design. When successful, SMRT assay showed 100% concordance with probe-extension assay at the family level and 98% at the individual level, with discordance attributable to allelic dropout inherent to both long-range PCR amplification and long-read sequencing. Analysis of the mutational spectrum confirmed 59dupC as the most prevalent mutation, affecting approximately 90% of families, while the other eight mutation types occurred at most twice. CONCLUSIONS: The SMRT assay outperformed the Clinical Laboratory Improvement Amendments-approved probe-extension assay by detecting essentially all VNTR-associated frameshift mutations. The probe-extension assay identified approximately 90% of affected families. MUC1fs immunohistochemistry added diagnostic value in genetically unresolved cases by detecting the pathogenic protein independent of the underlying mutation.
KEY POINTS: Retinoic acid receptor responder protein 1 is upregulated in proximal tubular epithelial cells in CKD. Soluble retinoic acid receptor responder protein 1 drives fibrosis by binding KH RNA binding domain conta...KEY POINTS: Retinoic acid receptor responder protein 1 is upregulated in proximal tubular epithelial cells in CKD. Soluble retinoic acid receptor responder protein 1 drives fibrosis by binding KH RNA binding domain containing, signal transduction associated 1, recruiting steroid receptor coactivator kinase, and inducing signal transducer and activator of transcription 3 phosphorylation. BACKGROUND: Kidney fibrosis is a hallmark of CKD, yet its underlying mechanisms remain incompletely understood. Retinoic acid receptor responder protein 1 (RARRES1) is largely restricted to podocytes in healthy kidneys but was upregulated within the tubulointerstitium in CKD. However, its functional contribution to kidney fibrosis remains unclear. METHODS: To assess the link between tubulointerstitial RARRES1 expression, eGFR, and fibrosis severity in patients with CKD, we analyzed multiple clinical datasets. RARRES1 upregulation in proximal tubular epithelial cells was confirmed in human CKD samples by immunofluorescence and RNAscope assays. Kidney fibrosis was evaluated in proximal tubule-specific Rarres1 knockout mice and RARRES1-overexpressing mice after CKD induction, including unilateral ureteral obstruction and folic acid-induced nephropathy. Mechanistically, mass spectrometry and coimmunoprecipitation, combined with truncation mutants, uncovered interactions among soluble RARRES1, KH RNA binding domain containing, signal transduction associated 1 (KHDRBS1), steroid receptor coactivator (Src) kinase, and phosphorylated signal transducer and activator of transcription 3 (STAT3). Pharmacologic blockade of STAT3 or Src kinase was used to evaluate the reversal of RARRES1-induced fibrotic phenotype. RESULTS: Multiple datasets revealed that tubulointerstitial RARRES1 expression correlated with decreased eGFR and increased fibrosis severity in patients with CKD. Immunofluorescence and RNAscope confirmed RARRES1 upregulation specifically in proximal tubular epithelial cells in CKD. Proximal tubule-specific knockout of Rarres1 significantly attenuated kidney fibrosis in two independent CKD models. Conversely, RARRES1-overexpressing mice showed aggravated kidney fibrosis compared with controls in the unilateral ureteral obstruction model. Soluble RARRES1 was identified as the key pathogenic form, with its plasma levels correlating with declining kidney function in patients with CKD. Mechanistically, soluble RARRES1 bound KHDRBS1, recruited Src kinase, and induced STAT3 phosphorylation at Tyr705, leading to upregulation of profibrotic factors. Inhibition of STAT3 or Src kinase partially reversed the fibrotic phenotype induced by RARRES1 overexpression. CONCLUSIONS: Our findings demonstrated that RARRES1 played an important role in regulating kidney fibrosis through the KHDRBS1/Src/p-STAT3 signaling axis.
Chen Q, Chen P, Liu L
… +17 more, Shi S, Zhou X, Yang H, Li Y, Guo L, Zhu S, Wang J, Bao Y, Zhang Q, Liu M, Ning X, Cai Y, He R, Liu Y, Wang Q, Lv J, Zhang H
KEY POINTS: Proteinuria responses to endothelin receptor antagonists and sodium-glucose cotransporter 2 inhibitors were not correlated. Ambrisentan-henagliflozin combination therapy reduced proteinuria similarly to ambri...KEY POINTS: Proteinuria responses to endothelin receptor antagonists and sodium-glucose cotransporter 2 inhibitors were not correlated. Ambrisentan-henagliflozin combination therapy reduced proteinuria similarly to ambrisentan monotherapy but exceeded henagliflozin alone. Combination therapy resulted in markedly less fluid retention and weight gain compared with endothelin receptor antagonist monotherapy. BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors and endothelin receptor antagonists (ERAs) can reduce proteinuria and may slow kidney progression in IgA nephropathy. Their potential synergistic efficacy and safety are unclear. METHODS: This open-label randomized crossover trial enrolled adults with IgA nephropathy, eGFR >30 ml/min per 1.73 m 2 , and 24-hour urine protein-creatinine ratio (UPCR) ≥0.44 g/g or 24-hour urine protein ≥0.5 g, despite maximal renin-angiotensin system blockade. Treatments were given in random order (ambrisentan 5 mg/d, henagliflozin 10 mg/d, and combination), each for 4 weeks followed by a 4-week washout. Primary end point was correlation between treatments in 24-hour UPCR changes. Secondary end points included eGFR change. Safety end points included fluid retention (body weight change). RESULTS: Sixty-five patients were enrolled, with a mean baseline eGFR of 69 ml/min per 1.73 m 2 (SD=23) and a median 24-hour UPCR of 0.8 g/g (0.6-1.3). No correlation was found in 24-hour UPCR reduction between single-agent therapy and combination therapy (ambrisentan, r =0.13, P = 0.97; henagliflozin, r =0.04, P = 1.00). After treatment, the mean reduction in 24-hour UPCR was -44% with combination therapy (95% confidence interval [CI], -52 to -34), which was similar to ambrisentan alone (-48%; 95% CI, -56 to -39) but significantly superior to henagliflozin alone (-21%; 95% CI, -33 to -6). The mean reduction in eGFR from baseline was -4.7 ml/min per 1.73 m 2 (95% CI, -6.9 to -2.6) with combination therapy, which was significantly greater than with ambrisentan (-0.5 ml/min per 1.73 m 2 ; 95% CI, -2.8 to 1.9) but comparable with henagliflozin (-3.5 ml/min per 1.73 m 2 ; 95% CI, -5.8 to -1.2). Less fluid retention occurred with combination treatment versus ambrisentan alone. CONCLUSIONS: Combining an ERA with an SGLT2 inhibitor further reduced proteinuria versus SGLT2 inhibitor alone, with less fluid retention than ERA alone. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR2400080435).
KEY POINTS: Neutrophil extracellular trap biomarkers were elevated and correlated with disease activity and complement deposition in thrombotic microangiopathy. Inhibiting neutrophil extracellular traps reduced organ inj...KEY POINTS: Neutrophil extracellular trap biomarkers were elevated and correlated with disease activity and complement deposition in thrombotic microangiopathy. Inhibiting neutrophil extracellular traps reduced organ injury and complement deposition through CD59 shedding in glomerular endothelial cells. BACKGROUND: Complement hyperactivation and endothelial cell damage are pivotal pathogenic drivers of multiple organ damage in complement-mediated thrombotic microangiopathy (TMA). The specific pathogenic role of neutrophil extracellular traps (NETs) remains unclear. METHODS: This study included 107 patients with complement-mediated TMA and measured circulating and renal NET biomarkers. The effects of peptidylarginine deiminase 4 ( Pad4 ) knockout, NET inhibitors (deoxyribonuclease I or GSK484), and neutrophil depletion were evaluated for their ability to attenuate multiorgan injury in complement-mediated TMA mice with a point mutation (W1206R) in complement factor H (FH R/R ). Furthermore, the influence of NETs on the regulation of the membrane attack complex (MAC), with a focus on CD59 modulation, was investigated in cultured human renal glomerular endothelial cells (HRGECs) and human umbilical vein endothelial cells. RESULTS: Elevated levels of NET biomarkers in both plasma and kidney tissues were observed in complement-mediated TMA patients, which were associated with disease activity and increased MAC deposition. In FH R/R mice, Pad4 knockout improved survival and attenuated phenotypes of TMA, as evidenced by the amelioration of anemia, kidney injury, MAC deposition, and macrovascular thrombosis. Therapeutic targeting of NETs with deoxyribonuclease I and PAD4 inhibitor GSK484 similarly ameliorated kidney pathology and MAC deposition in FH R/R mice. Neutrophil depletion significantly reduced systemic and kidney injury in FH R/R mice. NETs induced MAC deposition on HRGECs by promoting CD59 shedding through neutrophil serine proteases and enhanced coagulation through upregulation of tissue factor in human umbilical vein endothelial cells. Clinically, reduced glomerular CD59 expression and elevated urinary soluble CD59 levels were associated with both NET formation and MAC deposition. CONCLUSIONS: Levels of NET biomarkers increased in complement-mediated TMA and drove multiorgan injury by shedding CD59 from HRGECs to enhance complement activation and participate in coagulation activation.
KEY POINTS: De novo nephron regeneration was achieved after partial nephrectomy in axolotls. Tenascin C induction peaked at 2-4 weeks postpartial nephrectomy and coincided with cell proliferation and extracellular matrix...KEY POINTS: De novo nephron regeneration was achieved after partial nephrectomy in axolotls. Tenascin C induction peaked at 2-4 weeks postpartial nephrectomy and coincided with cell proliferation and extracellular matrix remodeling. Tenascin C-derived peptide 6, a tenascin C-derived matrikine, accelerated kidney regeneration by enhancing extracellular matrix remodeling and tenascin C expression. BACKGROUND: Kidneys possess limited regenerative capacity. While renal tubules are capable of repair after injury, nephron loss resulting from renal mass ablation or disease is irreversible in mammals. In this study, we demonstrated de novo nephron regeneration after partial nephrectomy in axolotls, a model organism renowned for its remarkable regenerative ability. METHODS: Kidney mass ablation was performed by using unilateral one-quarter partial nephrectomy in axolotls, and the regeneration process was assessed at multiple time points (0, 1, 2, 4, 8, 12, and 16 weeks) postsurgery. RESULTS: We found that cells migrated into the wound sites and proliferated, beginning at 1 week postnephrectomy and nearly restoring the cell mass of the contralateral kidney by 4 weeks. Cell proliferation peaked between weeks 2 and 4 at the resected site and was accompanied by fibroblast activation, SOX9 expression, and induction of tenascin C. By 16 weeks after nephrectomy, new glomeruli had formed and renal tubules were de novo regenerated and functionally matured. Notably, tenascin C expression was transiently induced, peaking at 2-4 weeks postsurgery and rapidly declined as cell repopulation progressed. Knockdown of tenascin C expression reduced cell proliferation and impaired regenerative process. Conversely, administration of tenascin C-derived peptide 6 shifted tenascin C expression to an earlier stage and accelerated both new nephron formation and functional maturation. CONCLUSIONS: These studies demonstrate de novo nephron regeneration after partial nephrectomy in an animal model and identify tenascin C-derived peptide 6 as an accelerator of kidney regeneration in vivo .
KEY POINTS: Lower urinary EGF levels, normalized to urinary creatinine, reflected impaired tubular health and were associated with higher kidney risk across CKD. Sodium-glucose cotransporter 2 inhibitors attenuated the d...KEY POINTS: Lower urinary EGF levels, normalized to urinary creatinine, reflected impaired tubular health and were associated with higher kidney risk across CKD. Sodium-glucose cotransporter 2 inhibitors attenuated the decline in urinary EGF-creatinine ratio observed with placebo, supporting a role in maintaining tubular health. Early increases in urinary EGF-creatinine ratio were linked to lower kidney risk, adding prognostic value beyond albuminuria. BACKGROUND: Urinary EGF is a marker of tubular repair capacity. Lower urinary EGF-creatinine ratio (uEGF/Cr) levels associate with kidney disease progression in patients with type 2 diabetes at early stages of CKD. In these patients, sodium-glucose cotransporter 2 inhibitors (SGLT2is) are associated with increased tubular EGF expression. In this study, we aimed to extend these findings to a broad CKD population with and without type 2 diabetes at various stages of CKD. METHODS: We measured EGF in stored urine samples at baseline and year 1 in participants from the Canagliflozin Cardiovascular Assessment Study (CANVAS), Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), and Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) clinical trials. Associations of baseline and longitudinal uEGF/Cr with the composite kidney outcome (sustained ≥40% eGFR decline, kidney failure, or kidney-related death) were assessed using multivariable Cox regression, and associations with annual eGFR decline using a two-slope linear mixed-effects model. Treatment effects of SGLT2i on uEGF/Cr over time were analyzed with analysis of covariance. RESULTS: In participants with type 2 diabetes from the CANVAS and CREDENCE trials ( N =5978), higher baseline uEGF/Cr was associated with a lower risk of the composite kidney outcome (hazard ratio per two-fold higher uEGF/Cr, 0.87 [95% confidence interval, 0.80 to 0.94]). SGLT2i attenuated the decline in uEGF/Cr over 1 year compared with placebo by 6.7% (95% confidence interval, 2.5 to 10.8). Increases in uEGF/Cr from baseline to year 1 were independently associated with a lower risk of the kidney outcome, even after accounting for 1-year changes in albuminuria, eGFR, and other clinical variables. Replication analyses showed similar results in the DAPA-CKD trial ( N =2450), with consistent findings in participants with and without diabetes. CONCLUSIONS: These results extend previous findings, supporting uEGF/Cr as a robust, independent biomarker of tubular health and kidney risk across diverse CKD populations. SGLT2i attenuated uEGF/Cr decline, and early changes in uEGF/Cr provided prognostic information beyond albuminuria.
J Am Soc Nephrol
· 2026 Jun · PMID 41926217
·
Full text
Autosomal dominant polycystic kidney disease is a systemic, hereditary disorder requiring life-long, multidisciplinary management. Approximately half of affected individuals progress to kidney failure by age 60 years. Re...Autosomal dominant polycystic kidney disease is a systemic, hereditary disorder requiring life-long, multidisciplinary management. Approximately half of affected individuals progress to kidney failure by age 60 years. Recent advances in genetics, imaging, and disease pathophysiology have enabled earlier diagnosis and improved risk stratification and led to the development of disease-modifying therapies (such as tolvaptan) for high-risk patients. Despite the availability of comprehensive clinical practice guidelines, real-world implementation is hindered by disease heterogeneity, psychosocial impacts, and the need for individualized care. The aim of this narrative review is to facilitate guideline implementation by integrating evidence from patient perspectives and real-world effectiveness and offering strategies to overcome practical barriers.