RESUMEN
BACKGROUND: Klotho and fibroblast growth factor 23 (FGF23) are key regulators of mineral metabolism in renal insufficiency. FGF23 levels have been shown to increase early in chronic kidney disease (CKD); however, the corresponding soluble Klotho levels at the different CKD stages are not known. METHODS: Soluble Klotho, FGF23, parathyroid hormone (PTH), 1,25-dihydroxy vitamin D(3) (1,25D) and other parameters of mineral metabolism were measured in an observational cross-sectional study in 87 patients. Locally weighted scatter plot smoothing function of these parameters were plotted versus estimated glomerular filtration rate (eGFR) to illustrate the pattern of the relationship. Linear and non-linear regression analyses were performed to estimate changes in mineral metabolism parameters per 1mL/min/1.73 m(2) decline. RESULTS: In CKD 1-5, Klotho and 1,25D linearly decreased, whereas both FGF23 and PTH showed a baseline at early CKD stages and then a curvilinear increase. Crude mean Klotho level declined by 4.8 pg/mL (95% CI 3.5-6.2 pg/mL, P < 0.0001) and 1,25D levels by 0.30 ng/L (95% CI 0.18-0.41 ng/L, P < 0.0001) as GFR declined by 1 mL/min/1.73 m(2). After adjustment for age, gender, serum 25-hydroxyvitamin D levels and concomitant medications (calcium, supplemental vitamin D and calcitriol), we estimated that the mean Klotho change was 3.2 pg/mL (95% CI 1.2-5.2 pg/mL, P = 0.0019) for each 1 mL/min/1.73 m(2) GFR change. FGF23 departed from the baseline at an eGFR of 47 mL/min/1.73 m(2) (95% CI 39-56 mL/min/1.73 m(2)), whereas PTH departed at an eGFR of 34 mL/min/1.73 m(2) (95% CI 19-50 mL/min/1.73 m(2)). CONCLUSIONS: Soluble Klotho and 1,25D levels decrease and FGF23 levels increase at early CKD stages, whereas PTH levels increase at more advanced CKD stages.
Asunto(s)
Progresión de la Enfermedad , Factores de Crecimiento de Fibroblastos/sangre , Glucuronidasa/sangre , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/fisiopatología , Índice de Severidad de la Enfermedad , Adulto , Anciano , Biomarcadores/sangre , Calcio/sangre , Estudios de Casos y Controles , Estudios Transversales , Femenino , Factor-23 de Crecimiento de Fibroblastos , Tasa de Filtración Glomerular/fisiología , Humanos , Proteínas Klotho , Masculino , Persona de Mediana Edad , Minerales/metabolismo , Hormona Paratiroidea/sangre , Fosfatos/sangre , Vitamina D/análogos & derivados , Vitamina D/sangreRESUMEN
BACKGROUND AND OBJECTIVES: Fibroblast growth factor 23 (FGF23) levels are elevated in patients with autosomal dominant polycystic kidney disease (ADPKD) and X-linked hypophosphatemia (XLH), but only the latter is characterized by a renal phosphate wasting phenotype. This study explored potential mechanisms underlying resistance to FGF23 in ADPKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: FGF23 and klotho levels were measured, and renal phosphate transport was evaluated by calculating the ratio of the maximum rate of tubular phosphate reabsorption to GFR (TmP/GFR) in 99 ADPKD patients, 32 CKD patients, 12 XLH patients, and 20 healthy volunteers. ADPKD and CKD patients were classified by estimated GFR (CKD stage 1, ≥90 ml/min per 1.73 m(2); CKD stage 2, 60-89 ml/min per 1.73 m(2)). RESULTS: ADPKD patients had 50% higher FGF23 levels than did XLH patients; TmP/GFR was near normal in most ADPKD patients and very low in XLH patients. Serum klotho levels were lowest in the ADPKD group, whereas the CKD and XLH groups and volunteers had similar levels. ADPKD patients with an apparent renal phosphate leak had two-fold higher klotho levels than those without. Serum klotho values correlated inversely with cyst volume and kidney growth. CONCLUSIONS: Loss of klotho might be a consequence of cyst growth and constrain the phosphaturic effect of FGF23 in most patients with ADPKD. Normal serum klotho levels were associated with normal FGF23 biologic activity in all XLH patients and a minority of ADPKD patients. Loss of klotho and FGF23 increase appear to exceed and precede the changes that can be explained by loss of GFR in patients with ADPKD.