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Letters to the Editor |
Calcium Metabolism and Osteoporosis Program American University of Beirut Medical Center Beirut, Lebanon Edward M. Brown, and Julian Seifter Divisions of Endocrinology (E.M.B.) and Nephrology (J.S.) Brigham and Women’s Hospital Boston, Massachusetts
Drs. Parfitt and Adami raise several interesting points in their letter above. Regarding the sigmoidal curves relating urinary excretion of Ca, Mg, and Na to serum Ca, our curve was fitted by a "mechanism-blind" computer program (1). While the data for Mg, Ca, and Na excretion on the low Na diet were not clearly sigmoidal, those for both Ca and Na excretion flattened out at higher serum Ca levels on the high Na diet. Moreover, the excretion rate for Mg became nearly constant above 1.6 mM Ca. Independent of the mechanism(s) involved, these sigmoidal curves approximate the data very closely (r2 > 0.9) on the high Na diet. While this may not square with the tenets of classic renal physiology, these were the results observed.
The issue then becomes understanding the difference between our observations and standard physiological teaching. In light of earlier work (2) on familial hypocalciuric hypercalcemia (FHH), which is caused by heterozygous inactivating mutations in the calcium-sensing receptor (CaR) (3), our results, coupled with the CaR’s localization and function along the nephron (4), argue that CaR-mediated inhibition of Na, Mg, and Ca reabsorption in the thick ascending limb (TAL) can explain Ca-induced increases in the excretion of these three ions (3). Attie et al. (2) has shown that parathyroidectomized patients with FHH exhibit marked flattening of the relationship between serum and urine Ca compared to those with hypoparathyroidism alone. This result strongly supports a key role for the CaR in mediating hypercalcemia-induced calciuria. We postulate that the normally steep slope of urine Ca on serum urine Ca does not so much reflect "saturation" of Ca reabsorption, with resultant "overflow" of urinary Ca, as it does CaR-mediated inhibition of this reabsorption. Persons with FHH also lack the usual natriuretic response to hypercalcemia, further implicating a renal action of the CaR at a site where Na and Ca handling are coupled, presumably the TAL (3). In the case of serum Ca-induced changes in urinary Mg and Na, because serum level of Na and Mg did not change during our study, their urinary excretion presumably plateaus at levels of serum Ca maximally stimulating the CaR, which occur at about 1.4–1.5 mM for CaR-mediated inhibition of PTH secretion.
Why doesn’t CaR-mediated inhibition of tubular Ca reabsorption produced a steeper, but still linear increase in Ca excretion? In studies performed in vivo, all relevant mechanism(s) cannot be dissected out; we agree with Drs. Parfitt and Adami that multiple factors may be at work. Ca-induced natriuresis may deplete plasma volume sufficiently to increase tubular Ca reabsorption, contributing to the curve’s sigmoidal shape. However, in the first two subjects studied in our clearance protocols, both PAH and inulin clearances were similar at the beginning and end of the citrate and calcium infusions, during both low salt and high salt protocols. Furthermore, in another study using a similar protocol, renal blood flow, as measured with para-aminohippurate clearance, was unchanged during either the calcium or the EDTA infusion in patients on a low-salt diet (5).
Complicating the situation further is the CaR’s presence elsewhere along the nephron [i.e. proximal and distal convoluted tubule and macula densa (4)], where it could also modulate Ca, Mg, and Na reabsorption. Additional studies utilizing existing transgenic models (e.g. mice with knockout of the CaR) and/or specific CaR agonists (6) or antagonists (7) will likely clarify further the CaR’s role in renal solute and water handling. Classic renal physiology, while based largely on "black-box" analyses of renal reabsorptive processes, has provided invaluable models for understanding renal function in the intact organism. The molecular tools are now available, however, for characterizing the mechanisms underlying renal tubular transport and relating these to in vivo observations.
Footnotes
Address correspondence to: Ghada El-Hajj Fuleihan, M.D., M.P.H., Director, Calcium Metabolism and Osteoporosis Program, American University of Beruit Medical Center, Bliss Street, P.O. Box 113-6044 Beirut, Lebanon.
Received January 12, 1999.
References
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