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 (IP). 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 (TRCa/GFR). In a clinical study, we set GFR equal to
creatinine clearance (Ccr) and IP equal to the urinary excretion rate of
phosphorus (EP). We employed EP/Ccr as a surrogate for [P]CDN. We showed that TRCa/Ccr 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 EP/Ccr before and
after treatment with
sevelamer carbonate or a placebo. All regressions were significant, and ∆[PTH] correlated with ∆EP/Ccr 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.