Kidney drug may reduce stone recurrence in cystinuria patients

Dilutional therapy with tolvaptan favourably alters cystine saturation in the urine and increases urine output in patients with cystinuria, as shown in a small study, suggesting the drug’s potential in reducing the recurrence of stones in this population.

“Dilutional therapy is the underlying foundation of cystinuria treatment based on the principle that adequate hydration will result in dilution of the fixed cystine load to a concentration below that at which crystallization typically occurs (through dietary modification, alkalization, and cystine-binding thiol drugs, [which] have had limited effectiveness),” according to investigators.

The selective arginine vasopressin V2-receptor antagonist tolvaptan prevents insertion of aquaporin channels in the apical membrane of collecting duct cells, resulting in decreased water absorption from the tubular lumen into the interstitium as well as increased urinary excretion of water, with minimal changes in electrolyte excretion. Its most common side effects include thirst and dry mouth, which help stimulate drinking. [J Clin Pharmacol 2014;54:1362-1367]

In effect, “vasopressin antagonist therapy has the potential to improve stone outcomes through its dilutional effect on the urine as well as stimulation of the thirst response, with resulting increases in fluid intake,” they explained. “[This is advantageous], as adequate oral hydration is difficult to achieve for many patients and compliance rates are low.” [J Urol 2003;169:68-70]

In the study, four cystinuria patients (two females: 17 and 23 years old; two males: 13 and 24 years old) received tolvaptan at low dose (0.3 mg/kg/day, maximum 30 mg) for 4 days and at high dose (0.6 mg/kg/day, maximum 60 mg) for another 4 days.

Cystine capacity respectively increased from −312, −82, −353, and −628 mg/L at baseline to 97, 111, 75, and −3 mg/L at day 8 following high-dose treatment. Additionally, 24-hour urinary volume rose from 1.96, 3.0, 2.1, and 0.91 L at baseline to 11.74, 6.5, 9.9, and 2.8 L at the same time point. [Urology 2020;144:65-70]

Serum electrolytes or liver enzymes remained stable. All patients reported experiencing extreme thirst (9/10 on visual analogue scale), but none discontinued treatment or reduced dose.

“As expected, response returned to baseline after cessation of tolvaptan, suggesting the effects are only seen during treatment, and are not cumulative,” the investigators noted. “V2-receptor antagonist therapy would need to be continuous and ongoing to be effective.”

However, long-term use of tolvaptan may be problematic, having been shown to induce liver injury in a minority of patients, the investigators acknowledged. This resulted in the Food and Drug Administration limiting the use of the drug for <30 days under a Risk Evaluation and Mitigation Strategy in patients with autosomal dominant polycystic kidney disease. [N Engl J Med 2012;367:2407-2418; bit.ly/3lMAblb]

“Further work would be needed to determine whether dilutional therapy with vasopressin antagonists would be a viable long-term treatment for cystinuria,” the investigators said. “This would include determination of optimal dosing to achieve the desired effect on cystine saturation, while maximizing tolerability [with respect to inducing thirst].”

Other agents in the selective V2-receptor antagonist class (ie, lixivaptan, mozavaptan, and satavaptan) should also be considered for treating cystinuria and may prove to be more suitable for this purpose, they added. [Int J Mol Sci 2019;21:183-190]