Table 5.
Performance of FGF23 and other systemic bone mineral markers against key analytical and clinical benchmarks
| Benchmark | Calcium | Phosphate | 25(OH)D | 1,25(OH)2D | PTH | FGF23 |
|---|---|---|---|---|---|---|
| Analytical criteria | ||||||
| Biologic stability (diurnal, postprandial, week to week, interracial) | Small magnitude diurnal variation and postprandial changes (23); minimal week-to-week variability (24,25,151) | Substantial diurnal and week-to-week variability (15%–35%) (24,150,152,153) and marked postprandial and postexercise excursions (23) | Marked seasonal (>100%) (26) and interracial variation (lower in African Americans than whites) (154,155) | Modest diurnal and week-to-week variability (26,156) | Very short plasma half-life (<4 min) (157), substantial diurnal (bimodal) and week-to-week variability (20%–40%) (153,158), greater variability in dialysis patients (25), significant interracial differences (higher in African Americans) (154,155) | iFGF23: short plasma half-life (<60 min) (159), significant diurnal (30%) and week-to-week variability (20%) (20,22); cFGF23: minimal intraindividual variability (20,39), minimal postprandial response (23,91); significant interracial differences (lower in African Americans than whites) (46,154) |
| Preanalytical issues | Total: venous stasis/hemoconcentration effects; free: pH and temperature dependence | Sample type differences; artifactual rise with delayed separation and hemolysis | Negligible | Negligible | Sample type-, method-, and time-dependent stability (160,161) | Sample type-, method-, and time-dependent stability (11,13) |
| Measure and homogeneity | Good | Good | Total D2+D3 or D3-specific methods; vitamin D binding protein bound and unbound fractions (bioavailable) (162) | Poorly characterized protein binding profile | Multiple fragments, method-dependent detection (32); partially characterized | C-terminal fragments variably present (20); poorly characterized |
| Between-method agreement | Good | Good | Poor; calibration differences; matrix effects caused by serum binding proteins (164); variable cross-reactivity with other hydroxylated vitamin D metabolites (33); isobaric interferences in MS methods (33) | Uncharacterized | Poor (165,166); calibration differences; no reference method; variable antibody specificity and affinities for different PTH peptides (167); cross-reactivity of intact assays for PTH (7–84)—overestimates bioactive fraction (168) | Poor; calibration differences (11,12); no reference method or ISP; variable fragment detection (20) |
| High-throughput testing | Yes | Yes | Yes | No | Yes | No |
| Cost per test (US)a | $8 | $8 | $30 | $40 | $30 | $40 |
| Clinical criteria | ||||||
| Temporality of change in CKD (3,34–36) | Variable | CKD stages 4 and 5 | Variable | CKD stages 2 and 3 | CKD stages 3 and 4 | CKD stages 2 and 3 |
| Robust and reproducible independent association with hard outcomes in multiple CKD studiesb | No (169) | Multiple studies link higher P to increased risk for CV disease and mortality (169–171) but not consistently (172) (Table 3) | Several studies report association of low levels with and mortality (173), although not consistently (Table 3); few assessing outcome with bioavailable fraction | Inconsistent in the small number of available studies, infrequently measured (Table 3) | Inconsistent (169) (Table 3); few studies assessing outcome with whole/bioactive evels | Consistent linear association with CV events, mortality, and progression to ESRD in multiple large prospective cohort studies; minimally confounded; substantial adjusted effect size (Table 2) |
| Specific clinicopathological correlates | Uncertain | Vascular toxin (174)? (vascular calcification; endothelial dysfunction); LVH (175)? Tubular toxicity (163)? | Deficiency linked to glomerular dysfunction (podocyte loss, glomerulosclerosis, albuminuria) and LVH (176)? | Uncertain | Variable association with bone histomorphometry (bone formation rate) except at extreme values (32) | LVMI and LVH (7,61–65) |
| Adds to or superior performance over existing testsc | — | — | Potential risk modifier (36) | Potential risk modifier (54,56) | — | Yes, improves discrimination and reclassification of risk associated with CV events and renal failure (42,45,47) |
| Validated decision limits in CKD | None | |||||
| Modifiable risk in CKD | Uncertain | |||||
| Variable response to therapy | ||||||
| Need to individualize therapy | ||||||
| Marker-guided therapy improves outcome in CKD | No evidence | |||||
MS, mass spectrometry; ISP, International Standard Preparation; CV, cardiovascular; LVH, left ventricular hypertrophy; LVMI, left ventricular mass index.
a
Approximate indicative commercial cost (including overheads).
b
Death or progression to ESRD requiring RRT.
c
Exisiting tests: calcium, phosphate, and PTH.