The role of intestinal oxalate transport in hyperoxaluria and the formation of kidney stones in animals and man

Abstract

The intestine exerts a considerable influence over urinary oxalate in two ways, through the absorption of dietary oxalate and by serving as an adaptive extra-renal pathway for elimination of this waste metabolite. Knowledge of the mechanisms responsible for oxalate absorption and secretion by the intestine therefore have significant implications for understanding the etiology of hyperoxaluria, as well as offering potential targets for future treatment strategies for calcium oxalate kidney stone disease. In this review, we present the recent developments and advances in this area over the past 10 years, and put to the test some of the new ideas that have emerged during this time, using human and mouse models. A key focus for our discussion are the membrane-bound anion exchangers, belonging to the SLC26 gene family, some of which have been shown to participate in transcellular oxalate absorption and secretion. This has offered the opportunity to not only examine the roles of these specific transporters, revealing their importance to oxalate homeostasis, but to also probe the relative contributions made by the active transcellular and passive paracellular components of oxalate transport across the intestine. We also discuss some of the various physiological stimuli and signaling pathways which have been suggested to participate in the adaptation and regulation of intestinal oxalate transport. Finally, we offer an update on research into Oxalobacter formigenes, alongside recent investigations of other oxalate-degrading gut bacteria, in both laboratory animals and humans.

Calcium Oxalate Nephrolithiasis and Gut Microbiota: Not just a Gut-Kidney Axis. A Nutritional Perspective

“…The gastrointestinal system plays a pivotal role in the pathophysiology of idiopathic calcium oxalate nephrolithiasis, the most common form of kidney stone disease [1][2][3]. Gut mucosa absorption consistently influences both calcium and oxalate metabolism and represents a fundamental driver of hypercalciuria and hyperoxaluria, the two most important pro-lithogenic urinary metabolic abnormalities found in calcium oxalate stone formers [4][5][6]. The concepts of "absorptive hypercalciuria" and "enteric hyperoxaluria" imply the presence of a cross-talk between the gut and the kidney contributing to the pathophysiology of calcium oxalate stones [4][5][6].…”

A randomised Phase II/III study to evaluate the efficacy and safety of orally administered Oxalobacter formigenes to treat primary hyperoxaluria

“…In humans, oxalate cannot be degraded and thus must be eliminated by the intestine and the kidneys. To avoid hyperoxalemia, animal experiments and experiments in human intestinal cell lines in vitro indicate that the body excretes oxalate through active transport from plasma to the gut [1–3] and transports oxalate in the renal tubuli by both passive osmotic and active processes [4]. Under physiological conditions, most oxalate is excreted by the kidneys; when kidney function is compromised, gut excretion appears to play a greater role [5, 6].…”

Oxalobacter formigenes treatment combined with intensive dialysis lowers plasma oxalate and halts disease progression in a patient with severe infantile oxalosis

“…Oxalobacter formigenes facilitates enteric elimination of oxalate through active and passive transport mechanisms [8] and may thus be capable of removing soluble oxalate from plasma to concentrations below the saturation threshold for calcium oxalate. This may subsequently result in the release of calcium and oxalate from systemic CaOx tissue deposits and plasma proteins.…”

“…Oxalobacter formigenes, an anaerobic commensal bacterium that uses oxalate as its sole carbon source [3], increases the active transcellular secretion of oxalate from the blood to the gastrointestinal tract through interaction with transporter proteins, possibly from the SLC26 family [8]. The bacterium is currently being developed as a potential treatment for PH in patients at different stages of renal function (Oxabact OC5; OxThera AB, Stockholm, Sweden) and has been shown to reduce Pox in PH patients [9,10].…”