Intestinal phosphate absorption: The paracellular pathway predominates?

Abstract

Hyperphosphatemia is nearly universal in patients with advanced chronic kidney disease and end stage renal disease. Given the considerable negative sequelae associated with hyperphosphatemia, i.e. increased cardiovascular disease, hastening of renal failure and death, reducing serum phosphate is a goal of therapy. In the absence of sufficient renal function, intestinal phosphate absorption is the remaining target to reduce plasma phosphate levels. Much work has been done with respect to understanding transcellular phosphate absorption. Both animal studies using inducible or intestinal NaPi-2b knockout mice and specific NaPi-2b inhibitors revealed this transporter as the primary mechanism mediating transcellular phosphate absorption in the intestine. However, this has not translated into effective phosphate lowering therapies in patients with kidney disease. More recently, it was observed that inhibition of the epithelial sodium hydrogen exchanger, sodium–hydrogen exchanger isoform 3 (NHE3), or its genetic deletion, decreases intestinal phosphate absorption. The mechanism mediating this effect is through increased transepithelial resistance and reduced paracellular phosphate permeability. Thus, NHE3 inhibition reduces paracellular phosphate permeability in the intestine. The transepithelial potential difference across intestinal epithelium is lumen negative and phosphate commonly exists as a divalent anion. Further, consumption of the typical Western diet provides a large lumen to blood phosphate concentration gradient. Based on these observations we argue herein that the paracellular phosphate absorption route is the predominant pathway mediating intestinal phosphate absorption in humans. Impact statement This review summarizes the work on transcellular intestinal phosphate absorption, arguing why this pathway is not the predominant pathway in humans consuming a “Western” diet. We then highlight the recent evidence which is strongly consistent with paracellular intestinal phosphate absorption mediating the bulk of intestinal phosphate absorption in humans.

Phosphate Control: The Next Frontier in Dialysis Cardiovascular Mortality

“…Considering high mortality rates in patients with CKD, particularly from CV causes, novel therapeutic innovations are necessary [4]. Given a growing evidence base that the dominant mechanism of phosphate absorption is the intestinal paracellular pathway [23, 53, 106], new therapies are investigating ways to reduce phosphate levels by blocking absorption through the paracellular pathway.…”

“…Although compensatory increases in parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) are initially sufficient to offset phosphate retention; these mechanisms are eventually overwhelmed [15-22]. Uncontrolled phosphate retention leads to elevated serum phosphate levels, or hyperphosphatemia, when the glomerular filtration rate falls to <30 mL/min/1.73 m 2 [23, 24]. This rate corresponds to CKD stages 4 and 5 [25].…”

“…Nicotinamide reduced phosphate concentrations in patients undergoing dialysis [104, 105], but a large proportion of study participants discontinued treatment due to adverse events [104]. Novel therapies targeting the paracellular pathway are logical, given a growing evidence base that the dominant mechanism of intestinal phosphate absorption is the paracellular pathway [23, 53, 106]. One such therapy is tenapanor, an investigational first-in-class nonbinder phosphate absorption inhibitor that targets the primary absorption pathway and provides a novel approach to treating hyperphosphatemia [106].…”

Phosphate Balance and CKD–Mineral Bone Disease

“…Dietary phosphate is absorbed passively via the nonsaturable paracellular pathway and actively via the saturable transcellular pathway. 54 , 117 , 118 , 119 Although it was previously believed that the active transcellular phosphate transport pathway was responsible for the majority of phosphate absorption, there is a growing body of evidence that the paracellular pathway is the dominant site of gastrointestinal phosphate absorption when luminal phosphate concentrations are high, 23 , 120 , 121 consistent with the consumption of a Western diet. 110 The paracellular route, in which phosphate passes through the tight junctions between the cell membranes, is the major phosphate absorption pathway under normal dietary conditions that contain high amounts of phosphate.…”

The Complexities of Organ Crosstalk in Phosphate Homeostasis: Time to Put Phosphate Sensing Back in the Limelight

“…Similarly, hypercalcitriolemia disorders (i.e., granulomatosis or inactivating mutations in CYP24A1, the gene encoding 24-hydroxylase), which would be expected to enhance NPT2B function, are not classically associated with hyperphosphatemia [ 44 ]. Based on these findings and other supporting evidence, such as the inefficiency of NPT2B inhibitors to correct hyperphosphatemia in CKD [ 45 ], it is now becoming accepted that the paracellular pathway is likely to be the dominant route for intestinal phosphate absorption [ 46 , 47 ]. It is proposed that tight junctions, and in particular the claudin family of proteins, may determine phosphate permeability [ 48 ].…”