Tradeoff-in-the-Nephron: A Theory to Explain the Primacy of Phosphate in the Pathogenesis of Secondary Hyperparathyroidism

Abstract

Chronic kidney disease (CKD) causes secondary hyperparathyroidism (SHPT). The cardinal features of SHPT are persistence of normocalcemia as CKD progresses and dependence of the parathyroid hormone concentration ([PTH]) on phosphate influx (I_P). The tradeoff-in-the-nephron hypothesis integrates these features. It states that as the glomerular filtration rate (GFR) falls, the phosphate concentration ([P]_CDN) rises in the cortical distal nephron, the calcium concentration ([Ca]_CDN) in that segment falls, and [PTH] rises to maintain normal calcium reabsorption per volume of filtrate (TR_Ca/GFR). In a clinical study, we set GFR equal to creatinine clearance (C_cr) and I_P equal to the urinary excretion rate of phosphorus (E_P). We employed E_P/C_cr as a surrogate for [P]_CDN. We showed that TR_Ca/C_cr was high in patients with primary hyperparathyroidism (PHPT) and normal in those with SHPT despite comparably increased [PTH] in each group. In subjects with SHPT, we examined regressions of [PTH] on E_P/C_cr before and after treatment with sevelamer carbonate or a placebo. All regressions were significant, and ∆[PTH] correlated with ∆E_P/C_cr in each treatment cohort. We concluded that [P]_CDN determines [PTH] in CKD. This inference explains the cardinal features of SHPT, much of the evidence on which other pathogenic theories are based, and many ancillary observations.

Keywords: calcium; chronic kidney disease; cortical distal nephron; distal convoluted tubule; parathyroid hormone; phosphate; secondary hyperparathyroidism.

Figure 1

Plots of E_Ca/C_cr and TR_Ca/C_cr against [PTH] in control subjects and patients with primary and secondary hyperparathyroidism (PHPT and SHPT). All data are derived from morning fasting specimens of urine and serum or plasma. Circles represent normal controls. Triangles and diamonds represent patients with PHPT and SHPT (CKD), respectively. Frame (a) shows that the lowest recorded values of E_Ca/C_cr in controls were compatible with normal [PTH]. It also shows that a minority of patients with CKD exhibited high E_Ca/C_cr and high [PTH] simultaneously. Frame (b) shows that [PTH] capable of causing high TR_Ca/C_cr in patients with PHPT maintained normal TR_Ca/C_cr in patients with CKD. Reproduced from [16] with permission of the publisher (Dustri-Verlag). E_Ca, Urinary excretion rate of calcium, mass/time; C_cr, Creatinine clearance (volume/time); TR_Ca, Rate of tubular reabsorption of calcium, mass/time; PTH, Parathyroid hormone; CKD, Chronic kidney disease.

Figure 2

Relationship of [PTH] to E_P/C_cr in sevelamer and placebo recipients. Squares pertain to the sevelamer group and diamonds to the placebo group. Graphs (a) and (c) show regressions of [PTH] on E_P/C_cr before and after administration of sevelamer carbonate for four weeks. Graphs (b) and (d) show the same regressions before and after administration of a placebo for four weeks. Graphs (e) and (f) show regressions of ∆[PTH] on ∆E_P/C_cr in the sevelamer and placebo groups, respectively, where “∆” = change during treatment. All regressions are statistically significant. Adapted from [17] with permission of the publisher (Dustri-Verlag). E_P, urinary excretion rate of phosphorus, mass/time; C_cr, creatinine clearance, volume/time.