Emerging evidence suggests that the majority of oxalate in the body is produced endogenously, with over 90% of urinary oxalate being synthesized internally rather than obtained from dietary sources.

This insight shifts the focus of kidney stone prevention from external dietary oxalate intake to the internal metabolic processes that contribute to oxalate production, particularly in individuals without major gastrointestinal surgery that would otherwise increase dietary oxalate absorption.

Oxidized Polyunsaturated Fatty Acids (PUFAs) and Oxalate Production
Linoleic acid, a commonly consumed polyunsaturated fatty acid (PUFA), undergoes non-enzymatic lipid peroxidation, leading to the formation of various oxidation products, including glyoxal. Glyoxal is hypothesized to be a significant precursor of endogenous oxalate synthesis in humans.

The conversion of glyoxal into oxalate represents a key metabolic pathway, linking lipid peroxidation of PUFAs like linoleic acid to kidney stone formation.

Several detoxifying enzymes, such as aldehyde dehydrogenase (ALDH), play a role in managing glyoxal levels, but when oxidative stress is high and the balance of reactive oxygen species is disturbed, the body’s ability to detoxify glyoxal may be overwhelmed.

This can lead to an accumulation of oxalate, a critical factor in the formation of kidney stones.

Oxidized LDL and Renal Injury
Beyond oxalate production, oxidized low-density lipoprotein (oxLDL) plays a direct role in kidney damage. OxLDL is a modified form of LDL that arises when lipoproteins containing PUFAs like linoleic acid become oxidized.

Studies have shown that oxLDL, but not native LDL, induces apoptosis (programmed cell death) in kidney cells known as podocytes. These cells play an essential role in maintaining the filtration barrier in the kidneys.

Their damage leads to glomerulosclerosis, which is essentially the arteriosclerosis of the kidneys—a condition marked by scarring and stiffening of the glomerular structures.

Human glomerular mesangial cells (HMCs), which provide structural support in the kidney’s glomerulus, also take up oxLDL under inflammatory conditions.

In the presence of inflammatory cytokines like Interleukin-1β (IL-1β), these HMCs ingest oxLDL beyond their scavenging capacity, becoming foam cells.

Foam cell formation in HMCs contributes to glomerulosclerosis and renal injury, further impairing kidney function and potentially exacerbating oxalate accumulation due to reduced renal filtration efficiency.

The connection between linoleic acid oxidation, endogenous oxalate production, and renal damage is a critical but often overlooked factor in kidney stone formation and progression of renal disease.

While dietary management of oxalate intake has traditionally been emphasized, reducing the intake of linoleic acid, and controlling oxidative stress within the body may be equally if not more important in mitigating the risk of kidney stones and protecting overall kidney health.