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

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). The tradeoff-in-the-nephron hypothesis integrates these features. It states that as the glomerular filtration rate (GFR) falls, the phosphate concentration ([P]) rises in the cortical distal nephron, the calcium concentration ([Ca]) in that segment falls, and [PTH] rises to maintain normal calcium reabsorption per volume of filtrate (TR/GFR). In a clinical study, we set GFR equal to creatinine clearance (C) and I equal to the urinary excretion rate of phosphorus (E). We employed E/C as a surrogate for [P]. We showed that TR/C 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/C before and after treatment with sevelamer carbonate or a placebo. All regressions were significant, and ∆[PTH] correlated with ∆E/C in each treatment cohort. We concluded that [P] 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.