{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T03:38:59Z","timestamp":1778125139479,"version":"3.51.4"},"reference-count":55,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T00:00:00Z","timestamp":1659312000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"\nBackground<\/jats:title>\nSecondary 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<\/jats:sub>]) rises, reduces the ionized calcium concentration in that segment ([Ca++<\/jats:sup>]DCT<\/jats:sub>), 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 (EP<\/jats:sub>\/Ccr<\/jats:sub>), a surrogate for [P]DCT<\/jats:sub>. In the present investigation, we estimated [P]DCT<\/jats:sub> from physiologic considerations and measurements of phosphaturia, and sought evidence for a specific chemical phenomenon by which increased [P]DCT<\/jats:sub> could lower [Ca++<\/jats:sup>]DCT<\/jats:sub> and raise [PTH].<\/jats:p>\n<\/jats:sec>\n\nMethods and findings<\/jats:title>\nWe studied 28 patients (\u201cCKD\u201d) with eGFR of 14\u201349 mL\/min\/1.73m2<\/jats:sup> (mean 29.9 \u00b1 9.5) and 27 controls (\u201cCTRL\u201d) with eGFR > 60 mL\/min\/1.73m2<\/jats:sup> (mean 86.2 \u00b1 10.2). In each subject, total [Ca]DCT<\/jats:sub> and [P]DCT<\/jats:sub> were deduced from relevant laboratory data. The Joint Expert Speciation System (JESS) was used to calculate [Ca++<\/jats:sup>]DCT<\/jats:sub> and concentrations of related chemical species under the assumption that a solid phase of amorphous calcium phosphate (Ca3<\/jats:sub>(PO4<\/jats:sub>)2<\/jats:sub> (am., s.)) could precipitate. Regressions of [PTH] on eGFR, [P]DCT<\/jats:sub>, and [Ca++<\/jats:sup>]DCT<\/jats:sub> were then examined. At filtrate pH of 6.8 and 7.0, [P]DCT<\/jats:sub> was found to be the sole determinant of [Ca++<\/jats:sup>]DCT<\/jats:sub>, and precipitation of Ca3<\/jats:sub>(PO4<\/jats:sub>)2<\/jats:sub> (am., s.) appeared to mediate this result. At pH 6.6, total [Ca]DCT<\/jats:sub> was the principal determinant of [Ca++<\/jats:sup>]DCT<\/jats:sub>, [P]DCT<\/jats:sub> was a minor determinant, and precipitation of Ca3<\/jats:sub>(PO4<\/jats:sub>)2<\/jats:sub> (am., s.) was predicted in no CKD and five CTRL. In CKD, at all three pH values, [PTH] varied directly with [P]DCT<\/jats:sub> and inversely with [Ca++<\/jats:sup>]DCT<\/jats:sub>, and a reduced [Ca++<\/jats:sup>]DCT<\/jats:sub> was identified at which [PTH] rose unequivocally. Relationships of [PTH] to [Ca++<\/jats:sup>]DCT<\/jats:sub> and to eGFR resembled each other closely.<\/jats:p>\n<\/jats:sec>\n\nConclusions<\/jats:title>\nAs [P]DCT<\/jats:sub> increases, chemical speciation calculations predict reduction of [Ca++<\/jats:sup>]DCT<\/jats:sub> through precipitation of Ca3<\/jats:sub>(PO4<\/jats:sub>)2<\/jats:sub> (am., s.). [PTH] appears to rise unequivocally if [Ca++<\/jats:sup>]DCT<\/jats:sub> 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.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0272380","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T19:00:02Z","timestamp":1659380402000},"page":"e0272380","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Chemical evidence for the tradeoff-in-the-nephron hypothesis to explain secondary hyperparathyroidism"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0684-9163","authenticated-orcid":true,"given":"Kenneth R.","family":"Phelps","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darren E.","family":"Gemoets","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0434-3855","authenticated-orcid":true,"given":"Peter M.","family":"May","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,8,1]]},"reference":[{"key":"pone.0272380.ref001","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/sj.ki.5002009","article-title":"Prevalence of abnormal serum vitamin D, PTH, calcium and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease","volume":"71","author":"A Levin","year":"2007","journal-title":"Kidney Int"},{"key":"pone.0272380.ref002","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/ki.1976.42","article-title":"Bone histology in incipient and advanced renal failure","volume":"9","author":"HH 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