Gut–kidney axis in oxalate homeostasis

Abstract

Purpose of review The gut–kidney axis plays a critical role in oxalate homeostasis, and better understanding of oxalate transport regulatory mechanisms is essential for developing novel therapies. Recent findings Oxalate potentially contributes to chronic kidney disease (CKD) progression, CKD - and end stage renal disease (ESRD)-associated cardiovascular diseases, polycystic kidney disease (PKD) progression, and/or poor renal allograft survival, emphasizing the need for plasma and urinary oxalate lowering therapies. One promising strategy would be to enhance the bowel's ability to secrete oxalate, which might be facilitated by the following findings. Oxalobacter formigenes (O. formigenes)-derived factors recapitulate O. formigenes colonization effects by reducing urinary oxalate excretion in hyperoxaluric mice by inducing colonic oxalate secretion. Protein kinase A activation stimulates intestinal oxalate transport by enhancing the surface expression of the oxalate transporter SLC26A6 (A6). Glycosylation also stimulates A6-mediated oxalate transport. The colon adapts to chronic acidosis in rats through increased colonic oxalate secretion as previously reported in CKD rats, and A6-mediated enteric oxalate secretion is critical in reducing the body oxalate burden in CKD mice. Intestinal oxalate transport is negatively regulated by proinflammatory cytokines and cholinergic, purinergic, and adenosinergic signaling. Summary These findings could facilitate the development of novel therapeutics for hyperoxalemia, hyperoxaluria, and related disorders if similar regulatory mechanisms are confirmed in humans.

Oxalate Homeostasis in Non-Stone-Forming Chronic Kidney Disease: A Review of Key Findings and Perspectives

“…Oxalate retention can initiate a vicious cycle of progressive kidney damage and a further decline in GFR. In turn, the formation of oxalate crystals in the kidneys can accelerate inflammation and scarring, leading to a decline in kidney function and contributing to the progression of CKD [ 56 , 64 ]. This interplay forms a vicious cycle between oxalate and CKD with shared risk factors, where each condition exacerbates the other by promoting the accumulation of oxalate in the body, ultimately leading to an increased risk of CKD progression ( Figure 2 ).…”

“…The gut–kidney axis is essential in maintaining oxalate homeostasis in CKD [ 5 , 31 , 64 , 97 ]. Despite extensive research, the precise mechanisms by which the kidneys and gut communicate to regulate oxalate homeostasis in CKD remain incompletely understood [ 31 ].…”

“…The presence of chronic inflammation caused by dysbiosis further exacerbates the decline in GFR, leading to reduced renal clearance of oxalate and the development of hyperoxalemia. In response to hyperoxalemia, enteric oxalate excretion becomes an important compensatory mechanism for maintaining oxalate homeostasis [ 2 , 13 , 64 ]. It has been hypothesized that in CKD, the intestine may adapt and increase the secretion of oxalate into the intestinal lumen by upregulating the expression of oxalate transporters [ 15 , 64 ].…”

“…In response to hyperoxalemia, enteric oxalate excretion becomes an important compensatory mechanism for maintaining oxalate homeostasis [ 2 , 13 , 64 ]. It has been hypothesized that in CKD, the intestine may adapt and increase the secretion of oxalate into the intestinal lumen by upregulating the expression of oxalate transporters [ 15 , 64 ]. A recent study on animal models of CKD found that the SLC26A6 oxalate transporter, which plays a key role in restricting net absorption by back-secreting oxalate into the lumen, is upregulated not only in the small intestine but also in the colon, resulting in increased oxalate removal through fecal excretion [ 15 ].…”

Pilot testing for long-term impact of glycerol-induced acute kidney injury on oxalate homeostasis in rats

“…Introduction. Cross-talk between gut microbiota and oxalate homeostasis is currently being actively discussed in scientific literature and has become the basis of global efforts to reduce the formation and progression of oxalate kidney stones [1][2][3][4]. Emerging evidence suggests that many gut bacteria (Oxalobacter formigenes, Enterococcus spp., Lactobacillus spp., Bifidobacterium spp., Bacillus spp) have the oxalate-degrading ability and points to their crucial role in oxalate homeostasis [1,[5][6][7].…”