FGF-23 and sFRP-4 in chronic kidney disease and post-renal transplantation

Abstract

Background: The phosphatonins fibroblast growth factor-23 (FGF-23) and FRP-4 are inhibitors of tubular phosphate reabsorption that may play a role in the hyperphosphatemia associated with chronic kidney disease (CKD) or in the hypophosphatemia associated with renal transplants.

Methods: Plasma FGF-23, FRP-4, phosphorus and parathyroid hormone were measured in patients at all stages of CKD. Phosphate regulation of FGF-23 and secreted frizzled related protein-4 (sFRP-4) was examined in end-stage renal disease patients in the presence and absence of therapeutic phosphate binder usage. In renal transplant patients, plasma FGF-23, sFRP-4 and phosphorus concentrations were determined before and 4-5 days after transplantation.

Results: Plasma FGF-23 correlated with creatinine clearance (r2 = -0.584, p < 0.0001) and plasma phosphorus (r2 = 0.347, p < 0.001) in CKD patients and with plasma phosphorus (r2 = 0.448, p < 0.001) in end-stage renal disease patients. Phosphate binder withdrawal increased FGF-23 levels. In kidney transplant patients, dramatic decreases in FGF-23 (-88.8 +/- 5.4%) and phosphorus (-64 +/- 10.2%) were observed by 4-5 days post-transplantation. In patients with post-transplant hypophosphatemia, FGF-23 levels correlated inversely with plasma phosphorus (r2 = 0.661, p < 0.05). sFRP-4 levels did not change with creatinine clearance or hyperphosphatemia in CKD or end-stage renal disease patients, and no relation was noted between post-transplant sFRP-4 levels and hypophosphatemia.

Conclusions: In CKD, FGF-23 levels rose with decreasing creatinine clearance rates and increasing plasma phosphorus levels, and rapidly decreased post-transplantation suggesting FGF-23 is cleared by the kidney. Residual FGF-23 may contribute to the hypophosphatemia in post-transplant patients.

Figure 1. Correlation of FGF-23 with creatinine clearance in CKD patients

A negative correlation was observed between log FGF-23 and creatinine clearance in CKD patients (n = 40, r² = - 0.584, p < 0.0001).

Figure 2. Mean FGF-23 levels in defined stages of CKD

FGF-23 levels (mean ± S.D.) are given for each stage of CKD defined by K DOQI guidelines and for ESRD patients.

Figure 3. Lack of relationship between FGF-23 and years on dialysis

Figure 4. Correlation between FGF-23 and plasma phosphorus in CKD patients

A positive correlation was seen between FGF-23 levels and plasma phosphorus (r² = 0.448, p < 0.001).

Figure 5. Correlation between FGF-23 and plasma phosphorus in ESRD patients

Log FGF-23 levels correlated positively with plasma phosphorus in CKD patients (r² = 0.346, p < 0.0001, n = 30).

Figure 6. Correlations of FGF-23 with plasma phosphorus and stages of chronic kidney disease

Correlations between FGF-23 and plasma phosphorus are shown for CKD stages 1-3 (r² = 0.089, NS, n = 21), CKD stages 4-5 (r² = 0.376, p < 0.01, n = 17) and ESRD (r² = 0.448, p < 0.001, n = 30).

Figure 7. Correlation between plasma FGF-23 and PTH

Log FGF-23 levels correlated positively with PTH levels in CKD patients (r² = 0.128, p = 0.02).

Figure 8. Effects of stopping and reinstating phosphate binders on plasma FGF-23 levels in ESRD patients

Basal levels of FGF-23 and plasma phosphorus were determined in hemodialysis patients (n = 6) taking phosphate binders to control hyperphosphatemia. Binder therapy was stopped, and FGF-23 levels were measured when plasma phosphorus levels increased to greater than 5.0 mg/dl (1-2 weeks; Washout). Binder therapy was then resumed, and FGF-23 levels were measured when plasma phosphorus fell to less than 4.5 mg/dl (1-2 weeks; Binders). All data are expressed as % basal and plotted as mean ± S.E.M.

Figure 9. Changes in FGF-23 and plasma phosphorus with kidney transplantation

Plasma levels of FGF-23 (A) and phosphorus (B) were measured within one day of renal transplant (pre) and 4 to 5 days post-transplant (post). Data are shown for individual patients. FGF-23 and plasma phosphorus decreased by 89% and 64%, respectively.

Figure 10. Plasma phosphorus in post-transplant hypophosphatemia correlates with FGF-23, but not PTH

In patients with post transplantation hypophosphatemia (plasma phosphorus ≤ 2 mg/dl), a correlation was observed between plasma phosphorus and FGF-23 levels (r² = 0.66, P < 0.05), but not PTH (r² = 0.250, p = NS) (n = 7).

Figure 11. Lack of correlation of sFRP4 levels with phosphorus, creatinine clearance, FGF-23 or calcium in CKD patients

Regression analysis revealed no statisticallv significant relationships of FRP-4 levels with (A) plasma phosphorus (r² = -0.003, NS). (B) creatinine clearance (r² = .046, NS). (C) FGF-23 (r² = 0.010, NS) or (D) calcium (r² = -0.002, NS). (n = 41).