Post-transplant hypophosphatemia: Tertiary ‘Hyper-Phosphatoninism’?

Abstract

Hypophosphatemia is a common complication of kidney transplantation. Tertiary hyperparathyroidism has long been thought to be the etiology, but hypophosphatemia can occur despite low parathyroid hormone (PTH) levels and can persist after high PTH levels normalize. Furthermore, even in the setting of normal allograft function, hypophosphatemia, and hyperparathyroidism, calcitriol levels remain inappropriately low following transplantation, suggesting that mechanisms other than PTH contribute. Fibroblast growth factor-23 (FGF-23) induces phosphaturia, inhibits calcitriol synthesis, and accumulates in chronic kidney disease. We performed a prospective, longitudinal study of 27 living donor transplant recipients to test the hypotheses that excessive FGF-23 accounts for hypophosphatemia and decreased calcitriol levels following kidney transplantation. Hypophosphatemia <2.5 mg/dl developed in 85% of subjects, including one who had previously undergone parathyroidectomy; 37% developed phosphate < or =1.5 mg/dl. The mean pre-transplant FGF-23 level was 1,218+/-542 RU/ml. Within the first week following transplantation, mean levels decreased to 557+/-579 RU/ml, which were still above normal. FGF-23 was independently associated with serum phosphate (P < 0.01), urinary excretion of phosphate (P < 0.01), and calcitriol levels (P < 0.01); PTH was not independently associated with any of these parameters. We calculated area under the curve for FGF-23 and PTH between the pre- and first post-transplant levels as a summary measure of early exposure to these phosphaturic hormones. An area under the FGF-23 curve greater than the median was associated with a relative risk of developing hypophosphatemia < or =1.5 mg/dl of 5.3 (P = 0.02) compared with lower levels. Increased area under the PTH curve was not associated with greater risk of hypophosphatemia. Excessive FGF-23 exposure in the early post-transplant period appears to be more strongly associated with post-transplant hypophosphatemia than PTH.

Recovery of Hyperphosphatoninism and Renal Phosphorus Wasting One Year after Successful Renal Transplantation

“…This observation strengthens the notion of inappropriate hyperphosphatoninism in the early posttransplant period as put forward in previous reports (3,4). After M3, however, FGF-23 levels showed a further decline to reach concentrations at M12 that were similar to those of CKD counterparts.…”

“…Persistence of inappropriately high serum levels of fibroblast growth factor-23 (FGF-23), a recently discovered phosphaturic hormone, plays an important role in the pathogenesis of this complication (3,4).…”

Fibroblast Growth Factor-23 and Parathyroid Hormone Are Associated with Post-Transplant Bone Mineral Density Loss

“…It is recognized that both hypophosphatemia and renal phosphate wasting may have a detrimental impact on bone mineralization (3,4). We and others recently reported that renal phosphate wasting in the post-transplant period is caused, at least partly, by the persistence of inappropriately high levels of fibroblast growth factor 23 (FGF-23) (5,6). This condition is often referred to as "tertiary hyperphosphatoninism."…”

The Journey From Vitamin D–Resistant Rickets to the Regulation of Renal Phosphate Transport

“…FGF23 levels are increased in chronic kidney disease (31, 80,85,86) and may be involved in the development of secondary hyperparathyroidism (87). FGF23 may also be important in the hypophosphatemia observed early after kidney transplantation and in nephrolithiasis associated with a renal leak of phosphate (88,89).…”