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Observational Study
. 2019 Apr 1;179(4):542-551.
doi: 10.1001/jamainternmed.2018.7980.

Association of Urinary Oxalate Excretion With the Risk of Chronic Kidney Disease Progression

Sushrut S Waikar  1 , Anand Srivastava  2 , Ragnar Palsson  1 , Tariq Shafi  3 , Chi-Yuan Hsu  4 , Kumar Sharma  5 , James P Lash  6 , Jing Chen  7   7 , Jiang He  7   7 , John Lieske  8 , Dawei Xie  9   10 , Xiaoming Zhang  9   10 , Harold I Feldman  9   10 , Gary C Curhan  1 ; Chronic Renal Insufficiency Cohort study investigators
Affiliations
Observational Study

Association of Urinary Oxalate Excretion With the Risk of Chronic Kidney Disease Progression

Sushrut S Waikar et al. JAMA Intern Med. .

Abstract

Importance: Oxalate is a potentially toxic terminal metabolite that is eliminated primarily by the kidneys. 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).

Objective: To assess whether urinary oxalate excretion is a risk factor for more rapid progression of CKD toward kidney failure.

Design, setting, and participants: This prospective cohort study assessed 3123 participants with stages 2 to 4 CKD who enrolled in the Chronic Renal Insufficiency Cohort study from June 1, 2003, to September 30, 2008. Data analysis was performed from October 24, 2017, to June 17, 2018.

Exposures: Twenty-four-hour urinary oxalate excretion.

Main outcomes and measures: A 50% decline in estimated glomerular filtration rate (eGFR) and end-stage renal disease (ESRD).

Results: This study included 3123 participants (mean [SD] age, 59.1 [10.6] years; 1414 [45.3%] female; 1423 [45.6%] white). Mean (SD) eGFR at the time of 24-hour urine collection was 42.9 (16.8) mL/min/1.73 m2. Median urinary excretion of oxalate was 18.6 mg/24 hours (interquartile range [IQR], 12.9-25.7 mg/24 hours) and was correlated inversely with eGFR (r = -0.13, P < .001) and positively with 24-hour proteinuria (r = 0.22, P < .001). During 22 318 person-years of follow-up, 752 individuals reached ESRD, and 940 individuals reached the composite end point of ESRD or 50% decline in eGFR (CKD progression). Higher oxalate excretion was independently associated with greater risks of both CKD progression and ESRD: compared with quintile 1 (oxalate excretion, <11.5 mg/24 hours) those in quintile 5 (oxalate excretion, ≥27.8 mg/24 hours) had a 33% higher risk of CKD progression (hazard ratio [HR], 1.33; 95% CI, 1.04-1.70) and a 45% higher risk of ESRD (HR, 1.45; 95% CI, 1.09-1.93). The association between oxalate excretion and CKD progression and ESRD was nonlinear and exhibited a threshold effect at quintiles 3 to 5 vs quintiles 1 and 2. Higher vs lower oxalate excretion (at the 40th percentile) was associated with a 32% higher risk of CKD progression (HR, 1.32; 95% CI, 1.13-1.53) and 37% higher risk of ESRD (HR, 1.37; 95% CI, 1.15-1.63). Results were similar when treating death as a competing event.

Conclusions and relevance: Higher 24-hour urinary oxalate excretion may be a risk factor for CKD progression and ESRD in individuals with CKD stages 2 to 4.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Waikar reported receiving grants from National Institutes of Health during the conduct of the study and grants and personal fees from Allena outside the submitted work. Dr Shafi reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Hsu reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Feldman reported receiving grants from the National Institutes of Health and personal fees from Kyowa Hakko Kirin Com and the National Kidney Foundation during the conduct of the study. Dr Curhan reported receiving grants, personal fees, and other from Allena Pharmaceuticals, personal fees from Shire, and other from UpToDate during the conduct of the study and personal fees from AstraZeneca and grants from Shoebox Audiometry outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Urinary Oxalate Excretion and the Risk of 50% Decline in Estimated Glomerular Filtration Rate (eGFR) or End-Stage Renal Disease According to Subgroups
The plot shows multivariable-adjusted hazard ratios (HRs) and 95% CIs (error bars) comparing quintiles 3 to 5 with quintiles 1 and 2. Cutoffs for continuous variables were chosen to represent medians or clinically relevant subgroups. Models are adjusted for age, sex, race/ethnicity, systolic blood pressure, diabetes, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), 24-hour urinary creatinine excretion, medications (phosphate binders, angiotensin II receptor blockers [ARBs], angiotensin-converting enzyme inhibitors [ACEIs], diuretics, β-blockers, statins, antiplatelet agents), hemoglobin, serum albumin, and baseline eGFR. To convert albumin to grams per liter, multiply by 10; to convert calcium to millimoles per liter, multiply by 0.25; and to convert phosphorus to millimoles per liter, multiply by 0.323.
Figure 2.
Figure 2.. Urinary Oxalate Excretion and the Risk of End-Stage Renal Disease According to Subgroups
The plot shows multivariable-adjusted hazard ratios (HRs) and 95% CIs (error bars) comparing quintiles 3 to 5 and quintiles 1 and 2. Cutoffs for continuous variables were chosen to represent medians or clinically relevant subgroups. Models are adjusted for age, sex, race/ethnicity, systolic blood pressure, diabetes, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), 24-hour urinary creatinine excretion, medications (phosphate binders, angiotensin II receptor blockers [ARBs], angiontensin-converting enzyme inhibitors [ACEIs], diuretics, β-blockers, statins, antiplatelet agents), hemoglobin, serum albumin, and baseline estimated glomerular filtration rate (eGFR). To convert albumin to grams per liter, multiply by 10; to convert calcium to millimoles per liter, multiply by 0.25; and to convert phosphorus to millimoles per liter, multiply by 0.323.
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