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.