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

BACKGROUND: Secondary hyperparathyroidism (SHPT) complicates advanced chronic kidney disease (CKD) and causes skeletal and other morbidity. In animal models of CKD, SHPT was prevented and reversed by reduction of dietary phosphate in proportion to GFR, but the phenomena underlying these observations are not understood. The tradeoff-in-the-nephron hypothesis states that as GFR falls, the phosphate concentration in the distal convoluted tubule ([P](DCT)]) rises, reduces the ionized calcium concentration in that segment ([Ca(++)](DCT)), and thereby induces increased secretion of parathyroid hormone (PTH) to maintain normal calcium reabsorption. In patients with CKD, we previously documented correlations between [PTH] and phosphate excreted per volume of filtrate (E(P)/C(cr)), a surrogate for [P](DCT). In the present investigation, we estimated [P](DCT) from physiologic considerations and measurements of phosphaturia, and sought evidence for a specific chemical phenomenon by which increased [P](DCT) could lower [Ca(++)](DCT) and raise [PTH]. METHODS AND FINDINGS: We studied 28 patients (“CKD”) with eGFR of 14–49 mL/min/1.73m(2) (mean 29.9 ± 9.5) and 27 controls (“CTRL”) with eGFR > 60 mL/min/1.73m(2) (mean 86.2 ± 10.2). In each subject, total [Ca](DCT) and [P](DCT) were deduced from relevant laboratory data. The Joint Expert Speciation System (JESS) was used to calculate [Ca(++)](DCT) and concentrations of related chemical species under the assumption that a solid phase of amorphous calcium phosphate (Ca(3)(PO(4))(2) (am., s.)) could precipitate. Regressions of [PTH] on eGFR, [P](DCT), and [Ca(++)](DCT) were then examined. At filtrate pH of 6.8 and 7.0, [P](DCT) was found to be the sole determinant of [Ca(++)](DCT), and precipitation of Ca(3)(PO(4))(2) (am., s.) appeared to mediate this result. At pH 6.6, total [Ca](DCT) was the principal determinant of [Ca(++)](DCT), [P](DCT) was a minor determinant, and precipitation of Ca(3)(PO(4))(2) (am., s.) was predicted in no CKD and five CTRL. In CKD, at all three pH values, [PTH] varied directly with [P](DCT) and inversely with [Ca(++)](DCT), and a reduced [Ca(++)](DCT) was identified at which [PTH] rose unequivocally. Relationships of [PTH] to [Ca(++)](DCT) and to eGFR resembled each other closely. CONCLUSIONS: As [P](DCT) increases, chemical speciation calculations predict reduction of [Ca(++)](DCT) through precipitation of Ca(3)(PO(4))(2) (am., s.). [PTH] appears to rise unequivocally if [Ca(++)](DCT) falls sufficiently. These results support the tradeoff-in-the-nephron hypothesis, and they explain why proportional phosphate restriction prevented and reversed SHPT in experimental CKD. Whether equally stringent treatment can be as efficacious in humans warrants investigation.