Oxalate as a potent promoter of kidney stone formation

Abstract

Kidney stones are among the most prevalent urological diseases, with a high incidence and recurrence rate. Treating kidney stones has been greatly improved by the development of various minimally invasive techniques. Currently, stone treatment is relatively mature. However, most current treatment methods are limited to stones and cannot effectively reduce their incidence and recurrence. Therefore, preventing disease occurrence, development, and recurrence after treatment, has become an urgent issue. The etiology and pathogenesis of stone formation are key factors in resolving this issue. More than 80% of kidney stones are calcium oxalate stones. Several studies have studied the formation mechanism of stones from the metabolism of urinary calcium, but there are few studies on oxalate, which plays an equally important role in stone formation. Oxalate and calcium play equally important roles in calcium oxalate stones, whereas the metabolism and excretion disorders of oxalate play a crucial role in their occurrence. Therefore, starting from the relationship between renal calculi and oxalate metabolism, this work reviews the occurrence of renal calculi, oxalate absorption, metabolism, and excretion mechanisms, focusing on the key role of SLC26A6 in oxalate excretion and the regulatory mechanism of SLC26A6 in oxalate transport. This review provides some new clues for the mechanism of kidney stones from the perspective of oxalate to improve the understanding of the role of oxalate in the formation of kidney stones and to provide suggestions for reducing the incidence and recurrence rate of kidney stones.

Keywords: SLC26A6; gut microbiome; hyperoxaluria; kidney stones; kindey; oxalate.

Figure 1

Absorption mechanism of oxalate in the intestine and kidney. Plasma oxalate is derived from endogenous oxalate produced by the liver and oxalate and its precursors absorbed by the intestine. In the intestine, dietary-derived oxalate promotes oxalate absorption through SLC26A3-mediated and paracellular absorption. SLC26A6-mediated oxalate secretion limits the net absorption of oxalate. Intestinal oxalate-degrading bacteria decompose oxalic acid to reduce the absorption of oxalic acid; calcium ions combine with oxalate to form insoluble calcium oxalate, which is not absorbed by the intestine and is excreted with feces, thus limiting the absorption of oxalate. Fatty acids reduce calcium combined with oxalate by binding to calcium, thereby promoting oxalate absorption. Oxalate excretion is assisted by the kidneys and intestine. In the kidney, oxalate is mainly excreted through glomerular filtration and can be assisted by SLC26A6-mediated oxalate secretion. Oxalate is in dynamic equilibrium under the influence of these factors. When some of these factors change, plasma oxalate concentration and urinary oxalate excretion increase, thereby promoting the formation of kidney stones.

Figure 2

Oxalate metabolism in the liver. In hepatocytes, various oxalate precursors are metabolized into the direct precursor glyoxylate, which is then converted to oxalate by LDH. Glyoxylate can be catalyzed by various enzymes to reduce oxalate production. AGT catalyzes the conversion of glyoxylate and alanine to pyruvate and glycine, and glyoxylate can be used by cytosolic glyoxylate reductase-hydroxypyruvate reductase (GRHPR) to produce glycolate. Glycolate can also be metabolized by glycolate oxidase (GO) to produce glyoxylate. HOGA catalyzes the conversion of 4-hydroxy-2- oxoglutarate (HOG) produced by hydroxyproline in mitochondria to produce pyruvate and glyoxylic acid. In the absence of AGT and GRHPR, glyoxylate accumulates in the liver to produce excessive oxalate, resulting in primary hyperoxaluria types 1 and 2. The mechanism by which the absence of HOGA causes primary hyperoxaluria type 3 is unknown. One theory suggests that 4-hydroxy-2-oxoglutarate is broken down into oxalates without HOGA, whereas another suggests that it inhibits GRHPR activity in mitochondria. Go, and LDH are emerging targets for RNA interference-based treatment of primary hyperoxaluria. AGT, Alanine-glyoxylate aminotransferase; GRHPR, Glyoxylate reductase–hydroxypyruvate reductase; HOGA, 4-Hydroxy-2-oxoglutarate aldolase; HOG, 4-Hydroxy-2-oxoglutarate; Go, Glycolate oxidase; LDH, Lactate dehydrogenase.

Figure 3

Regulation of slc26a6 oxalate transport activity.