Hypercalciuria and Nephrocalcinosis as Presenting Signs/Symptoms in HHRH: Potential Relevance to Phosphate Homeostasis in Normal People

In this article [Bergwitz et al., 2006: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1380228)(http://www.ncbi.nlm.nih.gov/pubmed/16358214)], Bergwitz et al. (2006) discussed the fact that nephrocalcinosis is often but not always a presenting symptom in hereditary hypophosphatemic rickets with hypercalciuria (HHRH). This is the third form of hypophosphatemia that I've read about and that results from mutations in nuclear DNA. In HHRH, there's hypofunctionality of one or another of the phosphate transporters that reabsorb filtered phosphate from the tubular fluid. The fact that nephrocalcinosis occurs before the people are ever treated with exogenous phosphate and occurs as a result of the phosphate depletion-induced elevations in calcitriol (1alpha,25-dihydroxyvitamin D, or 1,25-VD) provides some more indirect evidence that hypercalciuria is likely to contribute prominently to the nephrocalcinosis that can occur in people taking high doses of phosphate and hormonal vitamin D (or high doses of vitamin D) in combination [i.e. in X-linked hypophosphatemic rickets (XLHR) and autosomal dominant hypophosphatemic rickets]. Given that the physiological (endocrinological, etc.) conditions in HHRH are likely to, arguably, more closely mimic the conditions that would be present in a condition such as Fanconi syndrome (or even dietary phosphate depletion, to the extent that phosphate depletion could produce acidosis and mitochondrial damage in the proximal tubules), the research on HHRH suggests that the hypercalciuria that reliably accompanies significant dietary phosphate depletion (see past postings) (and the intracellular phosphate depletion that ultimately can result from it) could itself cause nephrocalcinosis.

In XLHR, part of the rationale for using calcitriol is to suppress the parathyroid hormone (PTH) release that can occur in response to the phosphate-induced decreases in serum calcium. In HHRH, there's no need to use calcitriol, because the serum calcium levels tend to be normal or elevated. And people who have HHRH display elevations in serum calcitriol levels, unless they're vitamin D deficient (severe but not mild vitamin D depletion decreases serum calcitriol, and vitamin D supplementation only increases serum calcitriol in people who are severely vitamin D deficient). The fact that normal vitamin D doesn't increase serum calcitriol past a certain point in normal people and can, at high dosages, actually decrease serum calcitriol (perhaps partly by increasing phosphate retention) is relevant to phosphate homeostasis in normal people. In my opinion, vitamin D (cholecalciferol, not calcitriol) at reasonable dosages (i.e. 2000-4000 IU/day or dosages that aren't high enough to potentially increase serum calcium and urinary calcium by much, if at all) could help to maintain low PTH levels in the context of reasonable increases in the dietary phosphate intake, in relation to the calcium intake. One reason it's desirable to maintain low serum PTH levels is that high PTH levels can increase urinary phosphate excretion and even, under extreme conditions, decrease the steady-state serum phosphate levels to a range that is below the baseline phosphate level (i.e. before the phosphate supplementation started). But that sort of derangement is more likely to occur, in my opinion, if one neglects magnesium homeostasis and doesn't take some reasonable but not massive amount of dietary calcium. I'm not much up for citing a bunch of articles today, but the point is that vitamin D can suppress PTH levels to a reasonable extent, much as calcitriol can [Barger-Lux et al., 1998: (http://scholar.google.com/scholar?hl=en&q=Barger-Lux+graded)], but can do so without the hypercalcemia and hypercalciuria that accompany calcitriol administration. Anyway, it's important to remember the potential that exists, in my view, for thrombogenic effects to result from even slight increases in serum calcium (such as in response to vitamin D, particularly orally-administered vitamin D) in people who have thrombogenic disorders or who are susceptible to that type of thing. Obviously, one would want to discuss this with one's doctor.