Oxalate homeostasis

Abstract

Oxalate homeostasis is maintained through a delicate balance between endogenous sources, exogenous supply and excretion from the body. Novel studies have shed light on the essential roles of metabolic pathways, the microbiome, epithelial oxalate transporters, and adequate oxalate excretion to maintain oxalate homeostasis. In patients with primary or secondary hyperoxaluria, nephrolithiasis, acute or chronic oxalate nephropathy, or chronic kidney disease irrespective of aetiology, one or more of these elements are disrupted. The consequent impairment in oxalate homeostasis can trigger localized and systemic inflammation, progressive kidney disease and cardiovascular complications, including sudden cardiac death. Although kidney replacement therapy is the standard method for controlling elevated plasma oxalate concentrations in patients with kidney failure requiring dialysis, more research is needed to define effective elimination strategies at earlier stages of kidney disease. Beyond well-known interventions (such as dietary modifications), novel therapeutics (such as small interfering RNA gene silencers, recombinant oxalate-degrading enzymes and oxalate-degrading bacterial strains) hold promise to improve the outlook of patients with oxalate-related diseases. In addition, experimental evidence suggests that anti-inflammatory medications might represent another approach to mitigating or resolving oxalate-induced conditions.

Fig. 1 |. Oxalate homeostasis.

a, Physiological oxalate homeostasis. Oxalate homeostasis is maintained by a delicate interplay of supply (that is, hepatic production, gastrointestinal (GI) absorption of dietary oxalate and tubular reabsorption of circulating oxalate) and excretion (GI secretion and faecal oxalate, glomerular filtration, tubular secretion and urinary oxalate). Physiological plasma oxalate concentrations of 1–5 μM have no known negative effects on the cardiovascular system. b, Disturbed oxalate homeostasis and the consequences of hyperoxalaemia. Oxalate homeostasis might be disturbed by alterations in numerous pathways. Plasma oxalate concentrations can increase owing to decreased urinary excretion in chronic kidney disease, increased hepatic production in primary hyperoxaluria or increased GI absorption in enteric hyperoxaluria. When kidney function is still sufficiently high to enable compensatory oxalate excretion in the kidney, hyperoxaluria can result in nephrocalcinosis, tubular toxicity and obstruction. Loss of kidney excretory function can lead to supersaturation of plasma with oxalate, which can have severe adverse effects on the cardiovascular system. High plasma oxalate is associated with sudden cardiac death, coronary artery disease, congestive heart failure and vascular calcification. Oxalate can also deposit in other tissues such as bone, thyroid, spleen and lungs.

Fig. 2 |. Model of endogenous oxalate synthesis pathways.

Glyoxylate links several metabolic pathways and is thought to be the principal precursor molecule of endogenous oxalate in healthy humans. Glyoxylate sources include hydroxyproline, which is derived from collagen metabolism and is metabolized to 4-hydroxy-2-oxoglutarate (HOG) and its reduced form 2,4-dihydroxyglutarate (DHG) via three steps in the mitochondrion; HOG can be converted to glyoxylate by 4-hydroxy-2-oxoglutarate aldolase type 1 (HOGA1). Deficiency of HOGA1 results in primary hyperoxaluria type 3 (PH3) but the exact mechanism by which oxalate accumulates in this condition is not clear. The accumulation of HOG might inhibit glyoxylate reductase/hydroxypyruvate reductase (GRHPR), which is ubiquitous in cytosol and mitochondria, and converts glyoxylate to glycolate; GRHPR deficiency causes PH2. The amino acid glycine is also converted to glyoxylate by d-amino acid oxidase (DAO) in the peroxisome. Deficiency of liver-specific, peroxisomal alanine–glyoxylate aminotransferase (AGT), which converts glyoxylate to glycine, results in PH1. In addition to glyoxylate, glycolate can be derived from sources such as glyoxal, which is a peroxidation product converted to glycolate by the glyoxalase system. Several other processes contribute to glycolate formation, including DNA repair (2-phosphoglycolate is converted to glycolate by phosphoglycolate phosphatase) and fructose or ethylene glycol metabolism (glycolaldehyde is converted to glycolate by aldehyde dehydrogenase). Glycolate is then converted to glyoxylate by liver-specific, peroxisomal glycolate oxidase (GO; also known as HAOX1). Glyoxylate is converted to oxalate by liver-specific lactate dehydrogenase A (LDHA).

Fig. 3 |. Oxalate transport in the small intestine.

Most oxalate absorption in the small intestine occurs passively through the paracellular pathway. Transcellular oxalate secretion is mediated by apical membrane Cl⁻–oxalate exchange through the transporter solute carrier family 26 member 6 (SLC26A6). The transporter on the basolateral membrane that operates in combination with apical SLC26A6 to mediate transcellular oxalate secretion in the small intestine has not yet been identified.

Fig. 4 |. Microbial modulation of oxalate homeostasis.

Dietary oxalate is degraded by several species of the intestinal microbiota, which can reduce the amount of oxalate available for intestinal absorption. Several bacterial species can degrade oxalate, including Oxalobacter formigenes, Escherichia coli, Bifidobacterium spp. and Lactobacillus spp. O. formigenes also releases a secretagogue that induces oxalate secretion into the gut. Several microbiome-based therapies are being developed to enhance oxalate degradation and reduce oxalate absorption in the gastrointestinal tract. These therapies include supplementation with oxalate-degrading bacterial communities, use of the enzyme oxalate decarboxylase, which metabolizes oxalate, and use of the E. coli Nissle strain, which has been genetically modified to encode the oxalate degradation pathway genes that encode oxalyl-CoA decarboxylase (oxdC) and formyl-CoA:oxalate CoA-transferase (frc).