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Controlled Diet Studies of Intestinal Phosphorus Absorption in Chronic Kidney Disease
Chronic kidney disease (CKD) affects approximately 37 million American adults with many more at risk for disease development. Elevated serum phosphorus and related abnormalities in phosphorus homeostasis due to progressive loss of kidney function are primary driving forces behind cardiovascular dysfunction and mortality in CKD patients. Intestinal phosphorus absorption is an understudied aspect in phosphorus homeostasis. Despite this lack of information, current therapies focus on reducing intestinal phosphorus absorption via the use of oral phosphate binders and dietary phosphorus restriction. Abnormalities in phosphorus-regulating hormones are already present in early stages of CKD, including elevated FGF23 and decreased 1,25-dihydroxyvitamin D, which should have the effect of reduced phosphorus absorption. However, rodent studies suggest that intestinal phosphorus absorption remains at inappropriately normal levels in CKD, despite perturbations in phosphorus homeostatic hormones. In these works, we studied intestinal phosphorus absorption in patients with CKD, with a particular emphasis on controlled diet studies, and on method of intestinal phosphorus absorption assessment.
In our first study, we assessed the variation and reliability of 24-hour urinary phosphorus excretion, a presumed biomarker of intestinal phosphorus absorption, in N=8 moderate-stage CKD patients. Here we found a high degree of variability in 13-consecutive measures of 24-hour urine phosphorus measures in patients consuming a controlled diet. We also found that at least two measures of 24-hour urine phosphorus is required for a reliable measure. Lastly, we found that in these moderate CKD subjects, 24-hour urine phosphorus is not related to net phosphorus absorption. However, this does not preclude the existence of a relationship in interventional studies assessing direct methods of intestinal phosphorus absorption suppression (i.e. efficacy studies of phosphorus binders) and urinary phosphorus excretion.
Next, we assessed fractional intestinal phosphorus absorption in N=8 moderate-stage CKD patients compared to N=8 healthy adults matched for age, sex, and race. In this study, we administered the radioisotopic tracer, 33-Phosphorus, via oral and intravenous routes, staggered by exactly 25-hours. This mimics the gold-standard method of dual-administration of two different isotopes. In our study, the use of a single isotope is a safer method as 33-Phosphorus is lower energy compared to 32-Phosphorus, a higher energy isotope used in some previous studies of end-stage kidney disease. Our results showed that fractional intestinal phosphorus absorption was similar between CKD patients and healthy adults, as we hypothesized. These findings were despite significantly lower values of serum 1,25D in CKD patients compared to healthy adults.
Lastly, we considered the effect of adherence to a low-phosphorus diet on serum phosphorus area-under-the-curve during the intradialytic period in hemodialysis patients. In this secondary analysis of a placebo-arm of a drug trial that included a controlled diet, we examined the post-dialytic serum phosphorus rebound in N=13 hemodialysis patients. We found that, compared to previous reports in the literature, adhering to a low-phosphorus diet in hemodialysis patients may delay the serum phosphorus rebound in the intradialytic period. In our study, only 2 of 13 patients had returned to their pre-dialysis serum phosphorus values at 24-hours post-dialysis and 4 of 13 at 48-hours. Importantly, all patients were not using phosphate binder medications for the duration of the study. These data show a potential benefit of adherence to a low phosphorus diet for phosphorus control, even in the absence of phosphate binder medications. However, longer studies of a controlled low phosphorus diet compared with a normal phosphorus diet on serum phosphorus rebound in the intradialytic period is needed to substantiate these findings.
The results from our studies are foundational in the understanding phosphorus absorption in moderate CKD. This knowledge will be critical for the development of translational interventions to limit phosphorus burden at earlier stages of the disease, thus limiting additional risk for disease progression and mortality.