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High urinary oxalate excretion intensifies CKD progression

Higher urinary excretion of oxalate increased the risk for chronic kidney disease progression and end-stage renal disease, according to research published in JAMA Internal Medicine.

“Oxalate is a potentially toxic terminal metabolite that is eliminated primarily by the kidneys,” Sushrut S. Waikar, MD, MPH, director of renal ambulatory services at Brigham and Women’s Hospital, and associate professor of medicine at Harvard Medical School, and colleagues wrote. “Oxalate nephropathy is a well-known complication of rare genetic disorders and enteric hyperoxaluria, but oxalate has not been investigated as a potential contributor to more common forms of chronic kidney disease (CKD).”

Waikar and colleagues conducted a prospective cohort study to determine if urinary oxalate excretion is associated with faster progression to kidney failure of among patients with CKD. The researchers recruited 3,123 patients with stages 2 to 4 CKD (mean age, 59.1 years; 45.3% women; 45.6% white) from the Chronic Renal Insufficiency Cohort study.

Participants collected urine samples for 24 hours prior to a study visit. The researchers used an oxalate oxidase enzymatic assay to measure urinary oxalate. They also assessed incident end-stage renal disease (ESRD), defined as receiving long-term dialysis or a kidney transplant, and CKD progression, defined as incident ESRD or a 50% decrease in estimated glomerular filtration rate (eGFR).

At the time of 24-hour urine collection, the mean eGFR was 42.9 mL/min/1.73 m². There was a median urinary excretion of oxalate of 18.6 mg/24 hours.

Urinary excretion of oxalate was inversely associated with eGFR (r = –0.13) and positively associated with 24-hour proteinuria (r = 0.22).

During follow-up, ESRD was present in 752 participants and CKD progression was observed in 940 participants.

Patients with higher oxalate excretion had greater risks for CKD progression and ESRD. Participants in the highest quintile of oxalate excretion ( 27.8 mg/24 hours) demonstrated a 33% higher risk of CKD progression (HR = 1.33; 95% CI, 1.04-1.7) and a 45% higher risk of ESRD (HR = 1.45; 95% CI, 1.09-1.93), compared with those in the lowest quintile (< 11.5 mg/24 hours).

There was a nonlinear association between oxalate excretion and CKD progression and ESRD, with a threshold effect at quintiles 3 to 5, compared with quintiles 1 and 2. Patients with a higher oxalate excretion had a 32% greater risk for CKD progression (HR = 1.32; 95% CI, 1.13-1.53) and 37% higher risk for ESRD (HR = 1.37; 95% CI, 1.15-1.63) than those with lower oxalate excretion.

“There is clinical plausibility to our findings of oxalate as a risk factor for CKD progression, considering the fact that rare genetic diseases of oxalate overproduction, enteric hyperoxaluria, and ethylene glycol ingestion are all well-recognized causes of kidney failure,” Waikar and colleagues concluded.

“If our results are confirmed, future research on pharmacologic or dietary measures to limit oxalate absorption and/or generation would be required to evaluate whether lowering urinary oxalate excretion is beneficial in CKD,” they added.

In an accompanying editorial, Joachim H. Ix, MD, MAS, chief of the division of nephrology-hypertension at the University of California, San Diego, wrote that the findings by Waikar and colleagues bring to light that even slightly raised oxalate exposure may advance kidney function loss in common forms of CKD.

“Factors that were associated with greater urine oxalate are consistent with known regulators of oxalate excretion and provide commonsense clues for new potential treatments,” he wrote. “Additional studies are also warranted to determine whether geographic variations in dietary oxalate in take may help explain differences in CKD prevalence worldwide.” – by Alaina Tedesco

Disclosures: Ix reports no relevant financial disclosures. Waikar reports receiving personal fees from Allena and grants from NIH. Please see study for all other authors’ relevant financial disclosures.