Oxalate (dys)Metabolism: Person-to-Person Variability, Kidney and Cardiometabolic Toxicity

Abstract

Oxalate is a metabolic end-product whose systemic concentrations are highly variable among individuals. Genetic (primary hyperoxaluria) and non-genetic (e.g., diet, microbiota, renal and metabolic disease) reasons underlie elevated plasma concentrations and tissue accumulation of oxalate, which is toxic to the body. A classic example is the triad of primary hyperoxaluria, nephrolithiasis, and kidney injury. Lessons learned from this example suggest further investigation of other putative factors associated with oxalate dysmetabolism, namely the identification of precursors (glyoxylate, aromatic amino acids, glyoxal and vitamin C), the regulation of the endogenous pathways that produce oxalate, or the microbiota's contribution to oxalate systemic availability. The association between secondary nephrolithiasis and cardiovascular and metabolic diseases (hypertension, type 2 diabetes, and obesity) inspired the authors to perform this comprehensive review about oxalate dysmetabolism and its relation to cardiometabolic toxicity. This perspective may offer something substantial that helps advance understanding of effective management and draws attention to the novel class of treatments available in clinical practice.

Keywords: cardiovascular disease; hyperoxaluria; hypertension; kidney disease; kidney stones; metabolic disease; microbiota; nephrolithiasis; obstructive sleep apnea; pharmacology; systemic inflammation.

Figure 1

Pathways of endogenous production of oxalate. Primary hyperoxaluria types 1 and 2 are respectively associated with peroxisomal AGT and cytosolic GRHPR deficiency, resulting in accumulation of glyoxylate, which is a precursor of oxalate. Primary hyperoxaluria type 3 is caused by a defect in HOGA at the mitochondria. Other precursors have been described as contributors to bioavailable oxalate including the aromatic aa (tryptophan and phenylalanine, which are essential AA obtained from diet), ascorbic acid/vitamin C (from diet) and glyoxal (from carbohydrate and lipid oxidation in erythrocytes and the liver). The mechanisms leading to increased oxalate levels in secondary hyperoxaluria are not so well defined as for primary oxaluria. Glyoxylate is converted into oxalate by several oxidases and dehydrogenases, including glyoxylate oxidase and lactate dehydrogenase (LDH). AGT, alanine-glyoxylate aminotransferase; GO, glycolate oxidase; GRHPR, glyoxylate reductase–hydroxypyruvate reductase; HOGA, 4-hydroxy-2-oxoglutarate aldolase; LDH, lactate dehydrogenase; aa amino acids. Created with BioRender.com.

Figure 2

Mechanisms and mediators of oxalate toxicity. The mechanisms that have been unveiled encompass a range of factors, including oxidative stress, disruption of mitochondrial function, inflammatory responses, endoplasmic reticulum stress, autophagy activation, and alteration of tissue structure as demonstrated by several hallmark molecular changes herein shown. Nox2, NADPH oxidase subunit 2; NQO1, NAD(P)H quinone dehydrogenase; SOD1, superoxide dismutase 1; GSH, glutathione GSH-Px, gluthatione peroxidase; CAT, catalase; MDA, malondialdehyde; GRP78, 78-kDa glucose-regulated protein; PERK, PKR-like ER kinase; IRE1, inositol-requiring enzyme 1; ATF6, Transcription factor 6; CHOP, C/EBP homologous protein; COX2, cyclooxygenase-2; NF-κB, Nuclear factor kappa light chain enhancer of activated B cells; Nalp3, Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing-3; IκB-α, NF-κB inhibitor α; SQSTM1/p62, Sequestosome-1/ubiquitin-binding protein p62; SA-βgal, β-galactosidase; TRF1, Telomeric repeat-binding factor 1; TRF1, Telomeric repeat-binding factor 2; POT1, Protection of telomeres protein 1; EMT, epithelial-to-mesenchymal transition. ↑ increase; ↓ decrease.