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The role of the paracellular pathway

Dr. Stuart Sprague describes our new mechanistic understanding of phosphate absorption.

Stuart M. Sprague, DO
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Transcript
00:03
Hello, everyone. I'm Dr. Stuart Sprague, Chief of Nephrology at North Shore University Health System and Professor of Medicine at the University of Chicago here in Chicago, Illinois. Today, I'm going to discuss advances in our mechanistic understanding of intestinal phosphate absorption and the role of the paracellular pathway. The average dietary intake of phosphorus is in the range of 1,500 milligrams daily. Approximately 65% of ingested phosphorus is absorbed in the small intestine.
00:36
Healthy kidneys excrete approximately 800 milligrams of excess phosphorus daily. The primary means of maintaining phosphate homeostasis is through the kidney's regulation of phosphate excretion. Consequently, phosphate regulation is highly dependent on kidney functions. While we understand how the body tries to maintain phosphate homeostasis, it wasn't until recently that we have begun to understand the mechanism by which dietary phosphorus absorption in the small intestine occurs.
01:07
Dietary phosphate absorption occurs in the gastrointestinal tract via two distinct pathways, transcellular transport and paracellular absorption. The paracellular pathway is a passive transport mechanism in which phosphate movement occurs along an electrochemical gradient through tight junction complexes between adjacent intestinal epithelial cells. Recent evidence suggests that in humans, the paracellular pathway is the primary mechanism of phosphate absorption in the gastrointestinal tract. Our evolving understanding of the primacy of the paracellular pathway is supported by several factors.
01:48
First, we now know that inorganic phosphate drives the electrochemical gradient in the intestine toward paracellular absorption. Second, unlike transcellular transport with NaPi2b, paracellular phosphate absorption does not saturate. Rather, paracellular phosphate absorption increases in a linear fashion with an increasing phosphate concentration gradient. The tight junctions in the paracellular space are composed of claudins. Claudins are proteins that form paracellular barriers and pores, which determine tight junction permeability toward individual or selected ion groups.
02:34
Under normal conditions, the claudins in the tight junctions allow phosphate to flow freely through the paracellular space, which is manageable when the kidney is capable of regulating serum phosphate levels, but can be problematic when the kidney function declines. As the science of intestinal phosphate absorption advances, it's becoming more evident that the paracellular pathway is the primary mechanism by which phosphate absorption occurs in humans. This new mechanistic understanding has important implications for the management of hyperphosphatemia.
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Indication

XPHOZAH (tenapanor) 30 mg BID is indicated to reduce serum phosphorus in adults with chronic kidney disease (CKD) on dialysis as add-on therapy in patients who have an inadequate response to phosphate binders or who are intolerant of any dose of phosphate binder therapy.

Important Safety Information

Contraindications

XPHOZAH is contraindicated in:

  • Pediatric patients under 6 years of age
  • Patients with known or suspected mechanical gastrointestinal obstruction

Warnings and precautions

Diarrhea

Patients may experience severe diarrhea. Treatment with XPHOZAH should be discontinued in patients who develop severe diarrhea.

Most Common Adverse Reactions

Diarrhea, which occurred in 43-53% of patients, was the only adverse reaction reported in at least 5% of XPHOZAH-treated patients with CKD on dialysis across trials. The majority of diarrhea events in XPHOZAH-treated patients were reported to be mild-to-moderate in severity and resolved over time, or with dose reduction. Diarrhea was typically reported soon after initiation but could occur at any time during treatment with XPHOZAH. Severe diarrhea was reported in 5% of XPHOZAH-treated patients in these trials.

For additional safety information, please see full Prescribing Information.

Indication

XPHOZAH (tenapanor) 30 mg BID is indicated to reduce serum phosphorus in adults with chronic kidney disease (CKD) on dialysis as add-on therapy in patients who have an inadequate response to phosphate binders or who are intolerant of any dose of phosphate binder therapy.

Important Safety Information

Contraindications

XPHOZAH is contraindicated in:

  • Pediatric patients under 6 years of age
  • Patients with known or suspected mechanical gastrointestinal obstruction

Warnings and precautions

Diarrhea

Patients may experience severe diarrhea. Treatment with XPHOZAH should be discontinued in patients who develop severe diarrhea.

Most Common Adverse Reactions

Diarrhea, which occurred in 43-53% of patients, was the only adverse reaction reported in at least 5% of XPHOZAH-treated patients with CKD on dialysis across trials. The majority of diarrhea events in XPHOZAH-treated patients were reported to be mild-to-moderate in severity and resolved over time, or with dose reduction. Diarrhea was typically reported soon after initiation but could occur at any time during treatment with XPHOZAH. Severe diarrhea was reported in 5% of XPHOZAH-treated patients in these trials.

For additional safety information, please see full Prescribing Information.

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