Dataset Information

Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD.

ABSTRACT: In CKD, phosphate retention arising from diminished GFR is a key early step in a pathologic cascade leading to hyperthyroidism, metabolic bone disease, vascular calcification, and cardiovascular mortality. Tenapanor, a minimally systemically available inhibitor of the intestinal sodium-hydrogen exchanger 3, is being evaluated in clinical trials for its potential to (1) lower gastrointestinal sodium absorption, (2) improve fluid overload-related symptoms, such as hypertension and proteinuria, in patients with CKD, and (3) reduce interdialytic weight gain and intradialytic hypotension in ESRD. Here, we report the effects of tenapanor on dietary phosphorous absorption. Oral administration of tenapanor or other intestinal sodium-hydrogen exchanger 3 inhibitors increased fecal phosphorus, decreased urine phosphorus excretion, and reduced [(33)P]orthophosphate uptake in rats. In a rat model of CKD and vascular calcification, tenapanor reduced sodium and phosphorus absorption and significantly decreased ectopic calcification, serum creatinine and serum phosphorus levels, circulating phosphaturic hormone fibroblast growth factor-23 levels, and heart mass. These results indicate that tenapanor is an effective inhibitor of dietary phosphorus absorption and suggest a new approach to phosphate management in renal disease and associated mineral disorders.

SUBMITTER: Labonte ED

PROVIDER: S-EPMC4413764 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD.

Labonté Eric D ED Carreras Christopher W CW Leadbetter Michael R MR Kozuka Kenji K Kohler Jill J Koo-McCoy Samantha S He Limin L Dy Edward E Black Deborah D Zhong Ziyang Z Langsetmo Ingrid I Spencer Andrew G AG Bell Noah N Deshpande Desiree D Navre Marc M Lewis Jason G JG Jacobs Jeffrey W JW Charmot Dominique D

Journal of the American Society of Nephrology : JASN 20141117 5

In CKD, phosphate retention arising from diminished GFR is a key early step in a pathologic cascade leading to hyperthyroidism, metabolic bone disease, vascular calcification, and cardiovascular mortality. Tenapanor, a minimally systemically available inhibitor of the intestinal sodium-hydrogen exchanger 3, is being evaluated in clinical trials for its potential to (1) lower gastrointestinal sodium absorption, (2) improve fluid overload-related symptoms, such as hypertension and proteinuria, in ...[more]

PMID: 25404658

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Project description:BackgroundReducing intestinal phosphorus absorption is a cornerstone in CKD-MBD management. Yet, knowledge gaps include how CKD pathophysiology affects intestinal phosphorus absorption. In vivo rodent studies suggest that intestinal phosphorus absorption remains inappropriately normal in early-moderate CKD, despite declining 1,25-dihydroxyvitamin D (1,25D). We measured intestinal phosphorus absorption in patients with moderate CKD versus healthy adults using a direct radiotracer method.MethodsPatients with CKD and healthy adults matched for age, sex, and race were enrolled in this 8-day controlled diet study: the first 6 days outpatient and the final 2 days inpatient. Oral and intravenous doses of 33P and serial blood and urine sampling determined intestinal phosphorus absorption during the final 2 days. Secondary outcomes included fasting biochemistries and 24-hour urine phosphorus (uP).ResultsIn total, n=8 patients with CKD (eGFR=29-55 ml/min per 1.73 m2) and n=8 matched healthy controls completed the study. On a controlled diet, no difference in fractional intestinal phosphorus absorption was detected between patients with CKD and healthy adults (0.69 versus 0.62, respectively; P=0.52), and this was similar for 24-hour uP (884 versus 935 mg/d, respectively; P=0.70). Fractional intestinal phosphorus absorption was not significantly related to 24-hour uP. Patients with CKD had higher serum intact PTH and intact FGF23 and lower 1,25D. The relationship between 1,25D and fractional intestinal phosphorus absorption was not statistically significant.ConclusionsIntestinal phosphorus absorption with typical dietary intake did not differ in patients with moderate CKD compared with controls, despite lower serum 1,25D levels. In this setting, a relationship between 24-hour uP and fractional or absolute intestinal absorption was not evident. Further investigation is needed to determine what factors influence intestinal phosphorus absorption in CKD and the apparent lack of compensation by the intestine to limit phosphorus absorption in the face of declining kidney function and reduced 1,25D. Whether this is evident across a range of dietary phosphorus intakes, as well as CKD severity, also needs to be determined.Clinical trial registry name and registration numberPhosphorus Absorption in Healthy Adults and in Patients with Moderate Chronic Kidney Disease, NCT03108222.

Dataset Information

Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD.

Publications

Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD.

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