Evidence for increased postprandial distal nephron calcium delivery in hypercalciuric stone-forming patients

Abstract

A main mechanism of idiopathic hypercalciuria (IH) in calcium stone-forming patients (IHSF) is postprandial reduction of renal tubule calcium reabsorption that cannot be explained by selective reduction of serum parathyroid hormone levels; the nephron site(s) responsible are not as yet defined. Using fourteen 1-h measurements of the clearances of sodium, calcium, and endogenous lithium during a three-meal day in the University of Chicago General Clinical Research Center, we found reduced postprandial proximal tubule reabsorption of sodium and calcium in IHSF vs. normal subjects. The increased distal sodium delivery is matched by increased distal reabsorption so that urine sodium excretions do not differ, but distal calcium reabsorption does not increase enough to match increased calcium delivery, so hypercalciuria results. In fact, urine calcium excretion and overall renal fractional calcium reabsorption both are high in IHSF vs. normal when adjusted for distal calcium delivery, strongly suggesting a distal as well as proximal reduction of calcium reabsorption. The combination of reduced proximal tubule and distal nephron calcium reabsorption in IHSF is a new finding and indicates that IH involves a complex, presumably genetic, variation of nephron function. The increased calcium delivery into the later nephron may play a role in stone formation via deposition of papillary interstitial apatite plaque.

Fig. 1.

Renal lithium handling in individual subjects. Serum lithium values (top left) and creatinine clearances (top right) did not differ between normal subjects (○) and idiopathic hypercalciuria with calcium stone (IHSF) patients (•), fasting or fed. Lithium clearance values (bottom left) of IHSF patients were above those of normal subjects, on average, in the fed state. Lithium excretion (bottom right) of IHSF patients and normal subjects did not differ on average; note that the one very high excretion value was from the subject with high serum lithium, so clearance values for this person were in the middle of the normal range.

Fig. 2.

Renal sodium handling in individual subjects. Symbols as in Fig. 1. Only distal sodium delivery (bottom left) differed between IHSF patients and normal subjects. Serum sodium and sodium filtered load (top) and sodium excretion (bottom right) did not differ between IHSF patients and normal subjects.

Fig. 3.

Renal calcium handling in individual subjects. Symbols as in Fig. 1. Distal calcium delivery and calcium excretion (bottom) were both higher in IHSF patients than in normal subjects during the fed state. Heterogeneity of IHSF is notable. Ultrafiltrate (UF) calcium and calcium filtered load (top) did not differ between IHSF and normal.

Fig. 4.

Relationship between distal calcium reabsorption, renal calcium excretion, and distal calcium delivery. Symbols as in Fig. 1. Distal calcium reabsorption (top left) rises with calcium delivery in normal subjects and IHSF patients. Values for both lie beneath the uppermost diagonal line of identity. Many IHSF reabsorption values lie beneath normal at overlapping values of distal calcium delivery, indicating a reduced fractional reabsorption of distally delivered calcium. The actual fraction (%) of distally delivered calcium excreted (top right) fell with increasing distal delivery, and points from many IHSF patients lie above normal points at comparable distal delivery; this panel visually amplifies the findings of panel at top left. Fractional and total calcium excretions, likewise, were high in many IHSF patients vs. normal subjects at comparable deliveries (bottom). Statistical analyses are in Tables 3 and 4.