Impaired Phosphate Tolerance Revealed With an Acute Oral Challenge

Abstract

Elevated serum phosphate is consistently linked with cardiovascular disease (CVD) events and mortality in the setting of normal and impaired kidney function. However, serum phosphate does not often exceed the upper limit of normal until glomerular filtration rate (GFR) falls below 30 mL/min/m 2 . It was hypothesized that the response to an oral, bioavailable phosphate load will unmask impaired phosphate tolerance, a maladaptation not revealed by baseline serum phosphate concentrations. In this study, rats with varying kidney function as well as normo-phosphatemic human subjects, with inulin-measured GFR (13.2 to 128.3mL/min), received an oral phosphate load. Hormonal and urinary responses were evaluated over 2 hours. Results revealed that the more rapid elevation of serum phosphate was associated with subjects and rats with higher levels of kidney function, greater responsiveness to acute changes in parathyroid hormone (PTH), and significantly more urinary phosphate at 2 hours. In humans, increases in urinary phosphate to creatinine ratio did not correlate with baseline serum phosphate concentrations but did correlate strongly to early increase of serum phosphate. The blunted rise in serum phosphate in rats with CKD was not the result of altered absorption. This result suggests acute tissue deposition may be altered in the setting of kidney function impairment. Early recognition of impaired phosphate tolerance could translate to important interventions, such as dietary phosphate restriction or phosphate binders, being initiated at much higher levels of kidney function than is current practice.

Acute Tissue Mineral Deposition in Response to a Phosphate Pulse in Experimental CKD

“…(2,5,10) Consistent with our findings, it has been previously hypothesized that in advanced CKD, there may be an attenuated PTH response to acute changes in serum phosphate that could negatively impact the body's capacity to acutely regulate the overall disposition of phosphate. (44) Importantly, the present results in the intact versus anephric conditions confirm that, within 30 minutes, three quarters of the phosphate is acutely cleared from the circulation via non-renal mechanisms, independent of acute changes in PTH and FGF-23. The mechanism of this short-term phosphate clearance appears to be mediated by tissue-based distribution, particularly into blood vessels, a mechanism that is further exacerbated by progressing by CKD with VC.…”

Twenty-Four-Hour Urine Phosphorus as a Biomarker of Dietary Phosphorus Intake and Absorption in CKD

“…Within subjects, 24-hour urine phosphorus was also negatively associated with whole-body phosphorus balance and not net phosphorus absorption. These results are corroborated by a recently published study by Turner et al (40), showing reduced urinary phosphorus excretion in adenine-induced CKD rats compared with healthy rats, which was not associated with a reduction in dietary phosphorus absorption, assessed by oral gavage of P-33 tracer. Turner et al argue similarly that tissue retention, not impaired absorption, was responsible for the lower urine phosphorus values seen in CKD.…”

Kidney Disease Progression Does Not Decrease Intestinal Phosphorus Absorption in a Rat Model of Chronic Kidney Disease–Mineral Bone Disorder

“…Further, in rats with adenine-induced CKD, the mild-CKD and severe CKD rats had similar appearance of 33 P into serum over 2 hours after an oral gavage compared with controls. (20) It is unclear whether differences in these rat experiments are the result of different stages of severity of the disease, or methodological differences in the in vitro versus in situ/in vivo absorption assessment techniques. This question is important to resolve, because if intestinal phosphorus absorption is in fact reduced with CKD, approaches targeting active intestinal phosphorus transport may be less effective than anticipated.…”