Fibroblast Growth Factor 23 and Kidney Disease Progression in Autosomal Dominant Polycystic Kidney Disease

Chonchol, Michel; Gitomer, Berenice; Isakova, Tamara; Cai, Xuan; Salusky, Isidro B.; Pereira, Renata C.; Abebe, Kaleab Z.; Torres, Vicente E.; Steinman, T.I.; Chapman, Arlene B.; Schrier, Robert W.; Wolf, Myles

doi:10.2215/cjn.12821216

Cited by 22 publications

(26 citation statements)

References 39 publications

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“…However, the variability in these rates of disease progression are comparable to numbers that were found in other cohort studies, such as the control groups in the TEMPO (Tolvaptan Efficacy and safety in Management of autosomal dominant Polycystic kidney disease and Its Outcome) 3:4 trial and the HALT-PKD (Halt Progression of Polycystic Kidney Disease) trials. 4 , 34 , 35 , 36 This variability in rate of disease progression emphasizes furthermore the correctness of the practical rationale of our study, i.e., that because of high variability in rate of disease progression, markers are needed to predict prognosis and select patients for treatment.…”

Section: Discussionmentioning

confidence: 68%

Urinary Biomarkers to Identify Autosomal Dominant Polycystic Kidney Disease Patients With a High Likelihood of Disease Progression

Messchendorp

Meijer

Boertien

et al. 2018

Kidney International Reports

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IntroductionThe variable disease course of autosomal dominant polycystic kidney disease (ADPKD) makes it important to develop biomarkers that can predict disease progression, from a patient perspective and to select patients for renoprotective treatment. We therefore investigated whether easy-to-measure urinary biomarkers are associated with disease progression and have additional value over that of conventional risk markers.MethodsAt baseline, inflammatory, glomerular, and tubular damage markers were measured in 24-hour urine collections (albumin, IgG, kidney injury molecule−1 (KIM-1), N-acetyl-β-d-glucosaminidase (NAG), β2 microglobulin (β2MG), heart-type fatty acid binding protein (HFABP), macrophage migration inhibitory factor (MIF), neutrophil gelatinase-associated lipocalin (NGAL), and monocyte chemotactic protein−1 (MCP-1). Disease progression was expressed as annual change in estimated glomerular filtration rate (eGFR, Chronic Kidney Disease EPIdemiology equation), measured glomerular filtation rate (mGFR, using 125I-iothalamate), or height-adjusted total kidney volume (htTKV). Multivariable linear regression was used to assess associations of these markers independent of conventional risk markers.ResultsA total of 104 ADPKD patients were included (40 ± 11 years, 39% female, eGFR 77 ± 30, mGFR 79 ± 30 ml/min per 1.73 m2 and htTKV 852 [510−1244] ml/m). In particular, β2MG and MCP-1 were associated with annual change in eGFR, and remained associated after adjustment for conventional risk markers (standardized β = −0.35, P = 0.001, and standardized β = −0.29, P = 0.009, respectively). Adding β2MG and MCP-1 to a model containing conventional risk markers that explained annual change in eGFR significantly increased the performance of the model (final R2 = 0.152 vs. 0.292, P = 0.001). Essentially similar results were obtained when only patients with an eGFR ≥ 60 ml/min per 1.73 m2 were selected, or when change in mGFR was studied. Associations with change in htTKV were less strong.ConclusionUrinary β2MG and MCP-1 excretion were both associated with GFR decline in ADPKD, and had added value beyond that of conventional risk markers. These markers therefore have the potential to serve as predictive tools for clinical practice.

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Section: Discussionmentioning

confidence: 68%

Urinary Biomarkers to Identify Autosomal Dominant Polycystic Kidney Disease Patients With a High Likelihood of Disease Progression

Messchendorp

Meijer

Boertien

et al. 2018

Kidney International Reports

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“…Participants in Study B (n5486) were 18-64 years of age with an eGFR of 25-60 ml/min per 1.73 m 2 (MDRD equation). Of these participants, n51002 participated in an FGF23 ancillary study (6) and had measurements of mineral metabolite levels (iFGF23, 1,25[OH] 2 D, 25[OH]D). An additional n5106 were missing PKD genotype and n532 were missing other covariates; thus n5864 were included in this analysis.…”

Section: Study Design and Participantsmentioning

confidence: 99%

“…All participants provided stored serum samples at their baseline visit, which were stored in a central repository at 280°C until they were shipped to the University of Washington for measurement of mineral metabolites. Serum iFGF23 was measured in duplicate using the Kainos immunoassay, which detects the full-length, biologically intact FGF23 molecule via midmolecule and distal epitopes, as described previously (6). The intra-and interassay coefficients of variability (CVs) are 3.8% and 3.0%, respectively, for this assay.…”

Section: Study Variablesmentioning

confidence: 99%

“…In the linear regression models, the dependent variables were annualized change in eGFR and mean annualized percentage change in htTKV, as calculated previously (6,9,12). The final multivariable linear models were adjusted for age; sex; race/ethnicity; study (A or B); randomization group; and baseline measurements of SBP, eGFR (CKD-EPI), BMI, urinary albumin excretion, serum calcium, and serum phosphorus.…”

Section: Statistical Analysesmentioning

confidence: 99%

“…Fibroblast growth factor 23 (FGF23) is a protein synthesized by bone and bone marrow cells that acts as a phosphaturic hormone, and also suppresses renal synthesis of 1,25-dihydroxyvitamin D (1,25[OH] 2 D) (4,5). We recently demonstrated that higher serum intact FGF23 (iFGF23) concentration was independently associated with adverse clinical end points in participants in the Halt Progression of Polycystic Kidney Disease (HALT-PKD) Studies (6). PKD mutation group (PKD1 truncating, PKD1 nontruncating, PKD2, or no mutation detected [NMD]) was also an important predictor of adverse clinical end points in HALT-PKD Study participants (7).…”

Section: Introductionmentioning

confidence: 99%

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Interactions between FGF23 and Genotype in Autosomal Dominant Polycystic Kidney Disease

et al. 2020

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BackgroundHigher serum intact fibroblast growth factor 23 (iFGF23) was associated with disease progression in participants with autosomal dominant polycystic kidney disease (ADPKD) in the HALT-PKD Studies. PKD mutation is also an important determinant of progression. We hypothesized that serum levels of iFGF23 and vitamin D metabolites (1,25-dihydroxyvitamin D [1,25(OH)2D] and 25-hydroxyvitamin D [25[OH]D]) differ according to ADPKD mutation and differentially predict clinical end points according to genotype (significant interaction between genotype and mineral metabolites).MethodsA total of 864 individuals with ADPKD who participated in the HALT-PKD Study A or B and had measurements of mineral metabolites (1,25[OH]2D, 25[OH]D, iFGF23) were categorized by PKD mutation (PKD1 truncating, PKD1 nontruncating, PKD2, or no mutation detected [NMD]). The association of the interactions of genotype × iFGF23, genotype × 1,25(OH)2D, and genotype × 25(OH)D with (1) annualized change in eGFR; (2) mean annualized percentage change in height-corrected total kidney volume (Study A only); and (3) time to a composite of 50% reduction in eGFR, ESKD, or death were evaluated using linear regression and Cox proportional hazards regression.ResultsMedian (interquartile range) iFGF23 differed (PKD1 truncating, 55.8 [40.7–76.8]; PKD1 nontruncating, 49.9 [37.7–71.0]; PKD2, 49.0 [33.8–70.5]; NMD, 50.3 [39.7–67.4] pg/ml; P=0.03) and mean±SD 1,25(OH)2D differed (PKD1 truncating, 32.8±12.8; PKD1 nontruncating, 33.4±12.5; PKD2, 34.1±13.1; NMD, 38.0±14.6 pg/ml; P=0.02) according to PKD genotype. There was a significant interaction between iFGF23 and genotype (P=0.02) for the composite end point in fully adjusted models, but no significant interaction between 1,25(OH)2D or 25(OH)D and genotype for clinical end points.ConclusionsADPKD genotype interacts significantly with FGF23 to influence clinical end points. Whereas the worst outcomes were in individuals with a PKD1-truncating or -nontruncating mutation and the highest iFGF23 tertile, risk of the composite end point differed according to iFGF23 the most in the PKD1-nontruncating and PKD2 groups.

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Interventions for preventing the progression of autosomal dominant polycystic kidney disease

St Pierre,

Cashmore,

Bolignano

et al. 2024

Cochrane Database of Systematic Reviews

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Fibroblast Growth Factor 23 and Kidney Disease Progression in Autosomal Dominant Polycystic Kidney Disease

Cited by 22 publications

References 39 publications

Urinary Biomarkers to Identify Autosomal Dominant Polycystic Kidney Disease Patients With a High Likelihood of Disease Progression

Urinary Biomarkers to Identify Autosomal Dominant Polycystic Kidney Disease Patients With a High Likelihood of Disease Progression

Interactions between FGF23 and Genotype in Autosomal Dominant Polycystic Kidney Disease

Interventions for preventing the progression of autosomal dominant polycystic kidney disease

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