Parathyroid Hormone, Fibroblast Growth Factor 23, and Parameters of Phosphate Reabsorption

Abstract

Background: The serum phosphorus concentration ([P]_s) is the sum of E_P/C_cr and TR_P/C_cr, where C_cr is creatinine clearance and E_P and TR_P are rates of excretion and reabsorption of phosphate. In chronic kidney disease (CKD), parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) mediate reduction of TR_P/C_cr, and [PTH] and [FGF23] are linear functions of E_P/C_cr. If controls and patients with CKD are considered together, TR_P/C_cr is a hyperbolic function of E_P/C_cr. Given these observations, we hypothesized that hyperbolas would describe relationships of phosphate reabsorption to [PTH] and [FGF23]. Methods: We studied 30 patients and 28 controls with mean eGFR of 29.5 and 86.0 mL/min/1.73 m², respectively. All analyses combined both subsets. We measured fasting [PTH] 1–84 and intact [FGF23], and determined contemporaneous E_P/C_cr, TR_P/C_cr, fractional excretion of phosphorus (FE_P), and phosphate tubular maximum per volume of filtrate (Tm_P/GFR). We examined linear regressions of TR_P/C_cr and Tm_P/GFR on 100/[PTH] and 100/[FGF23]; from linear equations we derived hyperbolic equations relating reabsorptive parameters to hormone concentrations. Results: TR_P/C_cr and Tm_P/GFR were linear functions of 100/[PTH] and 100/[FGF23] and hyperbolic functions of [PTH] and [FGF23]. TR_P/C_cr and Tm_P/GFR fell minimally over the ranges of E_P/C_cr, [PTH], and [FGF23] seen in CKD. FE_P rose with E_P/C_cr despite stable phosphate reabsorption. Conclusions: Hyperbolas describe relationships of TR_P/C_cr and Tm_P/GFR to [PTH] and [FGF23] if subjects with normal and reduced GFR are analyzed together. Although FE_P rises with [PTH] and [FGF23] as GFR falls, the simultaneous increments do not signify hormonally mediated reductions in phosphate reabsorption.

Chemical evidence for the tradeoff-in-the-nephron hypothesis to explain secondary hyperparathyroidism

“…The data considered herein were obtained before experimental interventions were initiated [ 12 , 13 , 24 , 25 ]. Aliquots of urine, serum, and plasma were obtained at a clinic visit occurring between 8:00 and 10:00 a.m.…”

“…The tradeoff-in-the-nephron hypothesis states that as GFR falls, [Ca ++ ] DCT also falls in response to increased total [P] DCT ; if [P] DCT reduces [Ca ++ ] DCT sufficiently, [PTH] rises to preserve Ca reabsorption and maintain normocalcemia [8]. Whereas the hypothesis was previously supported by significant relationships of [PTH] to E P /C cr , a surrogate for [P] DCT [12,13,24,25], the present study showed additionally that [Ca ++ ] DCT is related to total [P] DCT in CKD and CTRL (Figs 3A and 4A). If precipitation of amorphous Ca 3 (PO 4 ) 2 is posited in states of supersaturation, the results imply that in CKD, [PTH] increases as [P] DCT rises and [Ca ++ ] DCT falls.…”

“…Between 2010 and 2013, data were collected from 28 control subjects with estimated GFR (eGFR) > 60 mL/min/1.73m 2 and 30 patients with eGFR 14-49 mL/min/1.73m [12,13,24,25]. Aliquots of urine, serum, and plasma were obtained at a clinic visit occurring between 8:00 and 10:00 a.m.…”

“…If creatinine clearance (C cr ) is accepted as a surrogate for GFR, the ratio of the phosphorus excretion rate (E P ) to C cr quantifies the amount of P excreted per volume of filtrate. Moreover, E P /C cr is proportional to [P] DCT if fractional delivery of filtrate to the DCT is assigned a constant value [ 8 , 12 , 13 , 24 , 25 ]. In a cohort of 30 patients with stages G 3 or G 4 CKD, significant correlations between [PTH] and E P /C cr were demonstrated under multiple conditions, but a chemical mechanism to explain these correlations was not investigated [ 24 ].…”