Disentangling the Relationships Between the Renin–Angiotensin–Aldosterone System, Calcium Physiology, and Risk for Kidney Stones

Abstract

Context Complex relationships between aldosterone and calcium homeostasis have been proposed. Objective To disentangle the influence of aldosterone and intravascular volume on calcium physiology. Design Patient-oriented and epidemiology studies. Setting Clinical research center and nationwide cohorts. Participants/Interventions Patient-oriented study (n = 18): Participants were evaluated after completing a sodium-restricted (RES) diet to contract intravascular volume and after a liberalized-sodium (LIB) diet to expand intravascular volume. Cross-sectional studies (n = 3755): the association between 24h urinary sodium and calcium excretion and risk for kidney stones was assessed. Results Patient-oriented study: compared to a RES-diet, a LIB-diet suppressed renin activity (LIB: 0.3 [0.1, 0.4] vs. RES: 3.1 [1.7, 5.3] ng/mL/h; P < 0.001) and plasma aldosterone (LIB: 2.0 [2.0, 2.7] vs. RES: 20.0 [16.1, 31.0] vs. ng/dL; P < 0.001), but increased calciuria (LIB: 238.4 ± 112.3 vs. RES: 112.9 ± 60.8 mg/24hr; P < 0.0001) and decreased serum calcium (LIB: 8.9 ± 0.3 vs. RES: 9.8 ± 0.4 mg/dL; P < 0.0001). Epidemiology study: mean urinary calcium excretion was higher with greater urinary sodium excretion. Compared to a urinary sodium excretion of < 120 mEq/day, a urinary sodium excretion of ≥220 mEq/day was associated with a higher risk for having kidney stones in women (risk ratio = 1.79 [95% confidence interval 1.05, 3.04]) and men (risk ratio = 2.06 [95% confidence interval 1.27, 3.32]). Conclusions High dietary sodium intake suppresses aldosterone, decreases serum calcium, and increases calciuria and the risk for developing kidney stones. Our findings help disentangle the influences of volume from aldosterone on calcium homeostasis and provide support for the recommendation to restrict dietary sodium for kidney stone prevention.

Identification of the pivotal role of SPP1 in kidney stone disease based on multiple bioinformatics analysis

“…In addition, the pathway of aldosterone-regulated sodium reabsorption and AA metabolism were also significantly enriched. A recent study has revealed the influences of aldosterone and intra-vascular volume on calcium homeostasis and urinary calcium levels, suggesting the potential role of this pathway in KSD [ 25 ]. Baggio et al found higher contents of AA and prostaglandin E2 (PGE2) in plasma, higher urinary calcium excretion, as well as intestinal calcium absorption in idiopathic calcium stone formers compared to healthy controls [ 26 ].…”

Evaluating the clinical and mechanistic effects of eplerenone and amiloride monotherapy, and combination therapy with cinacalcet, in primary hyperparathyroidism: A placebo‐controlled randomized trial

“…There was also a lack of acute changes in PTH or ionized calcium over the course of 4 h from the time of drug dosing, suggesting that eplerenone was unable to induce an acute or chronic effect on PTH secretion in patients with P‐HPT. Since several studies have shown that volume status and/or urinary excretion of calcium may mediate the influence of aldosterone on PTH, 30,31 we also randomized participants to receive amiloride as an active comparator to eplerenone since it is a similar potassium‐sparing diuretic that can blunt the action of aldosterone in the distal nephron, but without interacting with the MR. Again, even though amiloride induced physiologically appropriate responses in BP, renin and aldosterone, there was no significant change in PTH, calcium or ionized calcium. Finally, in an open‐label extension phase, the addition of cinacalcet resulted in expected reductions in PTH and calcium; however, there were no synergistic effects of cinacalcet when combined with eplerenone or amiloride compared to placebo.…”

“…29 An alternative mechanism is that aldosteronism can induce a secondary hyperparathyroidism. Several studies have shown that changes in intravascular volume and/or sodium status, by virtue of changes in glomerular filtration and urinary excretion, can substantially modulate serum and urinary calcium levels in patients without P-HPT, 30,31 implying that changes in PTH in high aldosterone states may also be confounded by volume status and/or glomerular filtration.…”

Kidney Stone Prevention

“…High dietary sodium ingestion is accompanied by increased urinary calcium excretion [ 78 , 79 ] and CaOx crystal deposition in the kidney [ 80 , 81 ]. In pediatric patients, higher dietary sodium intake is also associated with calcium urolithiasis [ 82 ].…”