Evidence for net renal tubule oxalate secretion in patients with calcium kidney stones

Abstract

Little is known about the renal handling of oxalate in patients with idiopathic hypercalciuria (IH). To explore the role of tubular oxalate handling in IH and to evaluate whether differences exist between IH and normal controls, we studied 19 IH subjects, 8 normal subjects, and 2 bariatric stone formers (BSF) during a 1-day General Clinical Research Center protocol utilizing a low-oxalate diet. Urine and blood samples were collected at 30- to 60-min intervals while subjects were fasting and after they ate three meals providing known amounts of calcium, phosphorus, sodium, protein, oxalate, and calories. Plasma oxalate concentrations and oxalate-filtered loads were similar between patients (includes IH and BSF) and controls in both the fasting and fed states. Urinary oxalate excretion was significantly higher in patients vs. controls regardless of feeding state. Fractional excretion of oxalate (FEOx) was >1, suggesting tubular secretion of oxalate, in 6 of 19 IH and both BSF, compared with none of the controls (P < 0.00001). Adjusted for water extraction along the nephron, urine oxalate rose more rapidly among patients than normal subjects with increases in plasma oxalate. Our findings identify tubular secretion of oxalate as a key mediator of hyperoxaluria in calcium stone formers, potentially as a means of maintaining plasma oxalate in a tight range.

Fig. 1.

Individual results for hypercalciuric patients (●), bariatric patients (▴; both P), and normal subjects (N; ○). Fasting and fed plasma oxalate values (top left) overlapped among P and N. Fasting and fed urine oxalate excretion (top right) of P exceeded N (means, Table 2), and changes from fasting to fed were not significant (Table 2). Transepithelial oxalate concentration difference (TTOx) and fractional excretion of oxalate (FEOx) of P exceeded N (bottom) both fasting and fed (means, Table 2).

Fig. 2.

Lack of food dependence for main determinants of renal oxalate handling. Considering P (black circles) and N (grey circles), group means for fasting, breakfast to lunch (“Breakfast”), lunch to supper (“Lunch”), and supper to the end of the clearance periods (“Supper”) plasma oxalate, urine oxalate excretion, filtered load of oxalate and FEOx showed no sequential changes of statistical significance. Urine oxalate excretion and FEOx of P exceeded N (Table 2 and text). *P < 0.05 for P vs. N comparison within meal period.

Fig. 3.

Two measures of tubule oxalate handling. TTOx (y-axis) and FEOx (x-axis) correlate closely as expected from their equations that both contain the term urine oxalate molarity adjusted for the urine to serum ultrafiltrate creatinine concentrations. Urine oxalate excretion (UOx) is reflected in symbol size. Symbols for idiopathic hypercalciuria patients are black, N are grey, and bariatric stone formers (BSF) are triangles. Six patients (including both BSF) secrete oxalate by both measures and have the largest size symbols, denoting the highest oxalate excretion rates. All of the N, and the rest of the P show net oxalate reabsorption and, with the exception of 1 patient, have mean UOx rates below 30 μM/h (compare largest black dot in bottom left quadrant to legend).

Fig. 4.

P and N differ in the relationship between adjusted urine oxalate and plasma oxalate molarity. Urine oxalate adjusted for the urine-to-serum ultrafiltrate creatinine ratio (y-axis) varies with plasma oxalate (x-axis) in both P (black symbols) and N (grey symbols). Bariatric subjects are shown as triangles. Shown here are all clearance points for all subjects. Among P, the regression slope is far higher than N, as shown by the differences in the tilt of the nonparametric ellipses of containment (regression values and test for significance of slope difference in text). In general, the highest UOx (large points) cluster above the diagonal line of identity meaning net secretion is present.