Prognostic Value of Fibroblast Growth Factor 23 in Autosomal Dominant Polycystic Kidney Disease

Abstract

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst growth and a loss of functioning renal mass, but a decline in glomerular filtration rate (GFR) and onset of end-stage renal disease (ESRD) occur late in the disease course. There is therefore a great need for early prognostic biomarkers in this disorder. Methods: We measured baseline serum fibroblast growth factor 23 (FGF23) levels in 192 patients with ADPKD from the Consortium for Radiologic Imaging Studies of PKD (CRISP) cohort that were followed for a median of 13 years and tested the association between FGF23 levels and change over time in heightadjusted total kidney volume (htTKV), GFR, and time to the composite endpoints of ESRD, death, and doubling of serum creatinine. Results: Patients in the highest quartile for baseline FGF23 level had a higher rate of increase in htTKV (0.95% per year, P ¼ 0.0016), and faster rate of decline in GFR (difference of À1.03 ml/min/1.73 m 2 per year, P ¼ 0.005) compared with the lowest quartile, after adjusting for other covariates, including htTKV and genotype. The highest quartile of FGF23 was also associated with a substantial increase in risk for the composite endpoint of ESRD, death, or doubling of serum creatinine (hazard ratio [HR] of 2.45 in the fully adjusted model, P ¼ 0.03). Conclusion: FGF23 is a prognostic biomarker for disease progression and clinically important outcomes in ADPKD, and has additive value to established imaging and genetic biomarkers.

Response to “Fibroblast Growth Factor 23 Is a Valuable Predictor of Autosomal Dominant Polycystic Kidney Disease Progression”

“…Three studies, including ours, have now measured intact FGF23, using a 2-site enzyme-linked immunosorbent assay (either Kainos or Immutopics), and shown that it is unequivocally elevated. [2][3][4] Moreover, it is the intact form of FGF23 in the blood that is associated with progression of kidney volume growth and decline in glomerular filtration rate, as shown previously in the HALT study, 3 and now by us in CRISP. 4 More work is needed to unravel this fascinating puzzle, as well as to determine whether the association of FGF23 with outcomes represents a causal effect.…”

“…Indeed, severely polycystic livers were proved to produce and increase circulating FGF23 in ADPKD patients. 3 Overall, this study was very important, for it not only filled the gap by demonstrating what was not proved by the HALT-PKD Study which supported FGF23 use only in late ADPKD, 4 but also EI Ters et al showed predictive roles of FGF23 in ADPKD progression independent of chronic kidney disease. More mechanisms about FGF23 elevation in ADPKD will need to be studied.…”

Polycystic Kidney Disease Drug Development: A Conference Report

“… 19 A plethora of biomarkers have been shown to display associations with ADPKD disease progression, suggesting prognostic potential ( Table 1 ). 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 From an association standpoint, prognostic biomarkers should display a link with baseline eGFR and/or htTKV but also predict longitudinal growth in htTKV, decline in GFR, or time to kidney failure. Recent approaches to identify novel prognostic biomarkers have ranged from assessing disease severity based on the urine concentrating ability in patients after water deprivation 29 to looking at serum and urinary proteins, peptides, and metabolites.…”

Fibroblast Growth Factor 23 Is a Valuable Predictor of Autosomal Dominant Polycystic Kidney Disease Progression

“…To the Editor: We read the article "Prognostic Value of FGF23 in Autosomal Dominant Polycystic Kidney Disease" by El Ters and colleagues with great interest. 1 El Ters et al provided an important demonstration that serum FGF23 was a prognostic biomarker for kidney volume and renal outcomes or death in patients with early ADPKD. However, early elevation of FGF23 in ADPKD is complicated and remains inconclusive.…”

“…Experimental studies in PKD rodents revealed high FGF23 expression in the cyst-lining epithelium of kidneys but not in bone. 1 As kidney FGF23 does not contribute to the elevation of its circulating levels in uremia, 2 there may be other sources of high FGF23 in early ADPKD. Because ADPKD is a systemic disease, we assume that PKD mutations in different organs and tissues may produce FGF23 and lead to serum FGF23 elevation in humans.…”