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PubMed2026

Diagnostic and prognostic value of fibroblast growth factor 23 in acute kidney injury: systematic review and meta-analysis.

Background: Acute kidney injury (AKI) is associated with high mortality and adverse outcomes. Fibroblast growth factor 23 (FGF23) has emerged as a potential biomarker for AKI; however, its diagnostic and prognostic utility remains inconsistent.Methods: We conducted a systematic review and meta-analysis of studies evaluating circulating intact FGF23 (iFGF23) or C-terminal FGF23 (cFGF23) (PROSPERO: CRD42022302659). PubMed, EMBASE, CNKI, and Wanfang databases were searched through June 9, 2026. QUADAS-2 was used for quality assessment. A random-effects bivariate model pooled sensitivity, specificity, positive/negative likelihood ratio (PLR/NLR), diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic curve (SROC AUC).Results: Twenty-three studies were included: 17 diagnostic, 6 prognostic (one addressing both). For AKI diagnosis, the pooled sensitivity was 0.79 (95% CI 0.73-0.86), specificity 0.82 (95% CI 0.75-0.89), PLR 4.40 (95% CI 2.59-6.21), NLR 0.25 (95% CI 0.16-0.34), DOR 17.49 (95% CI 8.67-35.16), and SROC AUC 0.87 (95% CI 0.81-0.92). Substantial heterogeneity was observed (I2 = 67%), with iFGF23 demonstrating higher accuracy than cFGF23 (AUC 0.91 vs 0.81). For AKI mortality, pooled sensitivity was 0.77 (95% CI 0.69-0.84), specificity 0.76 (95% CI 0.70-0.82), DOR 10.89 (95% CI 6.86-17.30), and SROC AUC 0.77 (95% CI 0.70-0.83). Significant heterogeneity was noted (I2 = 86.2% for sensitivity, 80.4% for specificity). No significant publication bias was detected.Conclusions: Circulating FGF23 exhibits moderate-to-high diagnostic and moderate prognostic performance in AKI, though interpretation is limited by substantial heterogeneity. It may serve as a complementary biomarker for risk stratification, pending further validation with standardized protocols.

Humans↗

PubMed2026

Fibroblast Growth Factor 23 as a Prognostic Biomarker in Post-Myocardial Infarction Outcomes: Influence of Renal Function and Its Modulation by Klotho.

BACKGROUND: Elevation of FGF23 (fibroblast growth factor 23) and decreased Klotho levels have been associated with various cardiovascular and renal diseases. However, the combined study of the FGF23-Klotho axis in ischemic heart disease remains elusive. METHODS: We analyzed the associations between circulating FGF23 and Klotho levels with cardiac and renal parameters, as well as mortality outcomes following myocardial infarction (MI). Cardiac tissue from patients with ischemic heart disease and a post-MI mouse model were analyzed to assess myocardial FGF23 expression. Proteomic analysis was performed to examine myocardial pathways activated by FGF23 and regulated by Klotho. RESULTS: We observed an inverse correlation between circulating levels of FGF23 and Klotho in patients after MI. Elevated plasma FGF23 levels were particularly associated with ST-segment-elevation MI and cardiac dysfunction, including reduced left ventricular ejection fraction, prolonged corrected interval, and higher Killip-Kimball classification of cardiac risk, identifying FGF23 as a potential prognostic marker of overall and cardiac-related mortality. In contrast, systemic Klotho levels were reduced in patients with ST-segment-elevation MI but did not correlate with mortality. In cardiac tissue, ischemic injury significantly upregulated FGF23 expression. Although Klotho prevented FGF23-induced proteomic alterations, it did not inhibit cardiac FGF23 overexpression in the post-MI model. CONCLUSIONS: FGF23 represents a promising biomarker for mortality and cardiac dysfunction in patients with MI. Although Klotho does not appear to be a reliable predictor of mortality after MI, its cardioprotective properties suggest a role in modulating FGF23-driven metabolic, structural, and proliferative processes in the myocardium.

Fibroblast Growth Factor-23↗

PubMed2026

Hemophagocytic Lymphohistiocytosis and Fibroblast Growth Factor 23 (FGF23)-Induced Hypophosphatemia.

Hypophosphatemia is a frequent complication of chimeric antigen receptor T-cell therapy. In this setting, hypophosphatemia has been previously associated with cytokine release syndrome. The mechanisms underlying this electrolyte derangement are not fully understood. Extracellular phosphate consumption by chimeric antigen receptor T cells was demonstrated in vitro, but inflammation is also thought to play a contributing role. We present a case of severe, refractory hypophosphatemia with renal phosphate wasting triggered by hemophagocytic lymphohistiocytosis in acute lymphoblastic leukemia. The diagnosis of phosphate wasting was made at the onset of leukemia and a clinical exacerbation occurred after chimeric antigen receptor T-cell therapy. Diagnostic workup revealed very high fibroblast growth factor 23 (FGF23) levels in the absence of recognized acquired or genetic causes of impaired FGF23 cleavage. This case suggests that inflammation associated with hemophagocytic lymphohistiocytosis may induce FGF23 as a potential mechanism for hypophosphatemia. In this context, we recommend evaluation of renal phosphate wasting and subsequently FGF23 in patients with persistent hypophosphatemia despite standard supplementation.

Humans↗

PubMed2025

Network Interactions of Circulating FGF23, HRG-HMGB1, and Cardiac Disease in CKD.

KEY POINTS: Multitrait analysis of genome-wide association study boosts the statistical power to identify novel genetic traits for fibroblast growth factor 23. A functional genomics approach aided network discovery to identify histidine-rich glycoprotein (HRG) and high-mobility group protein box 1 (HMGB1) as key regulators of cardiac disease in CKD. Integration of clinical and genetic data enhances the discovery power and is crucial for understanding the genetic underpinnings of mineral bone disorder related to CKD. BACKGROUND: Genome-wide association studies (GWAS) have identified numerous genetic loci associated with mineral metabolism markers but have exclusively focused on single-trait analysis. In this study, we performed a multitrait analysis of GWAS (MTAG) of mineral metabolism, exploring overlapping genetic architecture between traits to identify novel genetic associations for fibroblast growth factor 23 (FGF23). METHODS: We applied MTAG to variants common to GWAS of five genetically correlated mineral metabolism markers in participants of European ancestry. We integrated UK Biobank GWAS for blood levels for phosphate, 25-hydroxyvitamin D, and calcium (n=366,484) and Cohorts for Heart and Aging Research in Genetic Epidemiology GWAS for parathyroid hormone (n=29,155) and FGF23 (n=13,716). We then used supervised and unsupervised deep machine learning to identify novel associations between genetic traits and FGF23. RESULTS: MTAG increased the effective sample size for mineral metabolism markers to n=50,325 for FGF23. After clumping, MTAG identified independent genome-wide significant single-nucleotide polymorphisms for all traits, including 62 loci for FGF23. Many of these loci have not been previously reported in single-trait analyses. Through a functional genomics approach, we identified histidine-rich glycoprotein (HRG) and high-mobility group box 1 (HMGB1) as master regulators of downstream canonical pathways associated with circulating FGF23, and both genes were highly enriched in hypertrophied cardiac tissue of deceased hemodialysis patients. In addition, we found that DNMT3A was associated with uremic toxin, 8-hydroxy-2-deoxyguanosine, a biomarker of DNA damage. In silico gene perturbation analysis revealed that DNMT3A is protective in patients with heart failure caused by hypertrophied or dilated cardiomyopathy. CONCLUSIONS: Our findings highlight the importance of MTAG analysis of mineral metabolism markers to boost the number of genome-wide significant loci for FGF23 to identify novel genetic traits. Functional genomics revealed novel networks that inform unique cellular functions and identified HRG and HMGB1 as key master regulators of FGF23 and cardiovascular disease in CKD.

bones, stones, and mineral metabolism↗

PubMed2025

Genetic evidence for repurposing GLP-1 receptor agonists in chronic kidney disease and IgA nephropathy: Metabolic and anti-inflammatory pathways beyond glycaemic control.

AIMS: Despite observational links between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and kidney benefits, causal mechanisms remain unclear. This study aims to dissect genetic causality and mediation pathways underlying the effects of GLP-1RAs on chronic kidney disease (CKD) and related renal outcomes. MATERIALS AND METHODS: Using large-scale Genome - Wide Association Study (GWAS) data, we applied two-sample Mendelian randomisation (MR) to estimate the causal effects of GLP-1RAs on CKD, estimated glomerular filtration rate (eGFR) and subtypes (IgA nephropathy, membranous nephropathy, nephrotic syndrome and chronic glomerulonephritis), with sensitivity analyses. The glycaemic markers (glycated haemoglobin [HbA1c] and blood glucose), type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) served as positive controls. Mediation MR assessed body mass index (BMI), lipids, glycaemic markers and inflammatory proteins. Data were sourced from MRC Integrative Epidemiology Unit Open Genome - Wide Association Studies OpenGWAS, FinnGen, GWAS Catalogue and cohort-specific studies. RESULTS: Positive control analyses revealed that genetically predicted GLP-1R activation was associated with reduced levels of HbA1c (p = 4.93E-15) and blood glucose (p = 9.73E-5), as well as a decreased risk of T2DM (p = 2.45E-4) and DN (p = 6.35E-4), fully validating the reliability of the genetic instruments. Genetic proxies for GLP-1R activation lowered risks of CKD (odds ratio [OR] = 0.83, p = 9.22E-9), immunoglobulin A nephropathy (IgAN) (OR = 0.70, p = 2.11E-3) and kidney function preservation (β = 0.01, p = 9.11E-3), but showed null effects on other CKD subtypes. Mediation analyses indicated that fibroblast growth factor 23 (FGF23) suppression mediated 26.57% of the effect on eGFR and 13.50% of CKD protection, whereas metabolic traits (BMI: 2.08% for CKD, 5.51% for eGFR; high-density lipoprotein: 0.79% for CKD, 2.34% for eGFR; HbA1c: 8.25% for eGFR) partially explained the benefits on CKD and eGFR. Only BMI exhibited a mediation effect on IgAN. Sensitivity analyses confirmed minimal pleiotropy. CONCLUSIONS: This study provides robust genetic evidence for repurposing GLP-1RAs in CKD and IgAN through anti-inflammatory (FGF23) and metabolic pathways, extending their utility beyond glucose control. While European ancestry data limit generalisability, our framework prioritises FGF23 and metabolic modulation as key targets for clinical trials in renal protection.

Humans↗

PubMed1978

Quantitative determination of the lateral diffusion coefficients of the hormone-receptor complexes of insulin and epidermal growth factor on the plasma membrane of cultured fibroblasts.

Fluorescent derivatives of insulin and epidermal growth factor bound to 3T3 mouse fibroblasts are mobile on the cell surface, with similar diffusion coefficients, D approximately (3--5) x 10(-10) cm2/sec at 23 degrees C. Increasing the temperature to 37 degrees C results in rapid receptor immobilization. The immobilization is attributed to aggregation of hormone-receptor complexes, their internalization, or a combination of both processes.

Azides↗

PubMed1978

Direct visualization of binding, aggregation, and internalization of insulin and epidermal growth factor on living fibroblastic cells.

We have studied in detail the binding of fluorescent derivatives of insulin and epidermal growth factor to 3T3 fibroblasts. We have used two types of fluorescent analogues of insulin and epidermal growth factor: highly fluorescent derivatives which have seven to eight rhodamine molecules or fluorescent derivatives which have a single rhodamine molecule per one molecule of insulin or epidermal growth factor. Both types of analogue retained substantial binding affinity as determined by radioreceptor assays and biological activity. The cells labeled with the fluorescent analogues were visualized with a sensitive video intensification microscopic system that enabled us to directly observe the location of the fluorescent hormone on the surface and within the living fibroblasts. We found that both insulin and epidermal growth factor initially bound diffusely to the cell surface and, at 4 degrees , remained dispersed. Within a few minutes at 23 degrees or 37 degrees the hormone-receptor complexes aggregated into patches that could be readily removed by trypsin but not by excess native hormone. The hormone-receptor complexes, which were initially mobile in the plane of the membrane, become immobilized later as the consequence of the receptor aggregation or internalization. Within approximately 30 min at 37 degrees , much of the labeled hormone was found within the cell in endocytic vesicles that moved about in the cytoplasm in a saltatory manner. The aggregation and immobilization of the hormone-receptor complexes could be due to either hormone-hormone interactions on the cell membrane or a hormone-induced conformational change in the hormone-receptor complex. Aggregation and internalization of hormone-receptor complexes could be associated with certain aspects of hormone action, hormone degradation, down regulation of receptors, or negative cooperativity of hormone binding.

Cell Line↗

PubMed1978

Collection of insulin, EGF and alpha2-macroglobulin in the same patches on the surface of cultured fibroblasts and common internalization.

We have used video intensification microscopy to observe fluorescent derivatives of insulin, epidermal growth factor and alpha2-macroglobulin added to Swiss 3T3-4 cells. At 4 degrees C, each of these polypeptides binds diffusely to specific receptors on the cell surface. When the cells are warmed to 23 or 37 degrees C, the bound insulin epidermal growth factor or alpha2-macroglobulin rapidly forms patches on the cell surface and is internalized. Using fluorescein-labeled alpha2-macroglobulin and rhodamine-labeled derivatives of insulin and epidermal growth factor, we show that all three polypeptides are internalized within the same vesicles by a common pathway. The mechanism for the internalization of these molecules is discussed.

Cell Line↗

PubMed1978

Primary avian tendon cells in culture. An improved system for understanding malignant transformation.

Primary avian tendon (PAT) cells which maintain their differentiated state in culture are rapidly transformed by Rous sarcoma virus. By criteria of morphology, increased rate of 2-deoxyglucose uptake, and loss of density dependent growth control, PAT cells transform as well as their less differentiated counterpart, chick embryo fibroblasts. In addition, the percentage of collagen produced by PAT cells drops on transformation by an order of magnitude, from 23 to 2.5%, but is unaffected by viral replication of a transformation-defective mutant. The responsiveness of normal and transformed PAT cells to various environmental factors changes dramatically upon transformation. Normal PAT cells respond to the presence of ascorbate and high cell density by raising the level of collagen synthesis from 5 to 23%. Transformed PAT cells are totally unresponsive. These and previously reported results lead us to postulate that the break-down in the normal regulatory mechanisms used by the cell to maintain the differentiated state is related to or is responsible for the onset of malignant transformation.

Animals↗