Kidney Week

Abstract: SA-PO265

Chemical Plausibility of the Tradeoff-in-the-Nephron Hypothesis

Session Information

• Bone and Mineral Metabolism: Calcium, Magnesium, Kidney Stones
  November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

• 402 Bone and Mineral Metabolism: Clinical

Authors

• Phelps, Kenneth R., Stratton Veterans' Affairs Medical Center, Albany, New York, United States

Kenneth R. Phelps,

• Mason, Darius, Methodist LeBonheur Healthcare, South Hospital, Albany, Tennessee, United States

Darius Mason,

Background

The tradeoff-in-the-nephron hypothesis attributes secondary hyperparathyroidism to events in the cortical distal nephron (CDN). The hypothesis suggests that high [HPO₄⁼]_CDN reduces [Ca⁺⁺]_CDN and thus necessitates high [PTH] for normal Ca reabsorption (Nutrients 2017;9:427). We sought further evidence for the hypothesis with regressions of [PTH] on inferred values of [HPO₄⁼]_CDN and 1/[Ca⁺⁺]_CDN.

Methods

Fasting data were obtained from 30 patients with CKD (mean eGFR 29.5) and 28 controls (mean eGFR 85.9). To estimate concentrations in the CDN, we assumed fractional delivery (k) of filtrate = 0.2 in controls and 0.35 in CKD; Ca delivery = 0.1(eGFR)[Ca]_uf, ([Ca]_uf = plasma ultrafilterable Ca); and P delivery = urinary P excretion (E_P). We assumed pH in the CDN = 6.5 and pK of the H₂PO₄^- Û HPO₄⁼ equilibrium = 6.8. From the Henderson-Hasselbalch equation, we estimated delivery of HPO₄ to the CDN as 0.33(E_P). We calculated [Ca]_CDN as (0.1)(eGFR[Ca]_uf)/k(eGFR) and [HPO₄]_CDN as (0.33)(E_P/C_cr)(eGFR)/k(eGFR), where E_P/C_cr = P excretion per volume of filtrate = [P]_u[cr]_p/[cr]_u.
We assumed that CaHPO₄ Û Ca⁺⁺ + HPO₄⁼ in the CDN, with K_sp = 10^-7. Since equimolar amounts of Ca and P associate to form CaHPO₄, we let complexed [Ca] and [HPO₄] = z. We calculated ionized [Ca⁺⁺]_CDN as ([Ca]_CDN – z) and ionized [HPO₄⁼]_CDN as ([HPO₄]_CDN – z). Since [Ca⁺⁺]_CDN*[HPO₄⁼]_CDN = K_sp, we inferred that ([Ca]_CDN – z)([HPO₄]_CDN – z) = 10^-7, and solved for z with the quadratic formula after algebraic manipulation. For CKD and controls, we examined linear regressions of [PTH] on [HPO₄]_CDN, 1/[Ca]_CDN, ([HPO₄]_CDN – z), and 1/([Ca]_CDN – z).

Results

In CKD, regressions of [PTH] on [HPO₄]_CDN, ([HPO₄]_CDN – z), and 1/([Ca]_CDN – z) were significant; the regression of [PTH] on 1/[Ca]_CDN was not significant (see Table). In controls, only the regression of [PTH] on 1/[Ca]_CDN was significant.

Conclusion

In CKD (but not controls), [PTH] is related directly to ionized and total [HPO₄]_CDN, and inversely to ionized but not total [Ca]_CDN. The effect of [HPO₄⁼]_CDN on [PTH] appears to be mediated by [Ca⁺⁺]_CDN.

Funding

• Veterans Affairs Support – Genzyme