Potential Pharmacologic Treatments for Cystinuria and for Calcium Stones Associated with Hyperuricosuria

Abstract

SummaryTwo new potential pharmacologic therapies for recurrent stone disease are described. The role of hyperuricosuria in promoting calcium stones is controversial with only some but not all epidemiologic studies demonstrating associations between increasing urinary uric acid excretion and calcium stone disease. The relationship is supported by the ability of uric acid to "salt out" (or reduce the solubility of) calcium oxalate in vitro. A randomized, controlled trial of allopurinol in patients with hyperuricosuria and normocalciuria was also effective in preventing recurrent stones. Febuxostat, a nonpurine inhibitor of xanthine oxidase (also known as xanthine dehydrogenase or xanthine oxidoreductase) may have advantages over allopurinol and is being tested in a similar protocol, with the eventual goal of determining whether urate-lowering therapy prevents recurrent calcium stones. Treatments for cystinuria have advanced little in the past 30 years. Atomic force microscopy has been used recently to demonstrate that effective inhibition of cystine crystal growth is accomplished at low concentrations of L-cystine methyl ester and L-cystine dimethyl ester, structural analogs of cystine that provide steric inhibition of crystal growth. In vitro, L-cystine dimethyl ester had a significant inhibitory effect on crystal growth. The drug's safety and effectiveness will be tested in an Slc3a1 knockout mouse that serves as an animal model of cystinuria.

What Is the Best Method to Evaluate Urine pH? A Trial of Three Urinary pH Measurement Methods in a Stone Clinic

“…9 There is therefore a fairly narrow therapeutic window that requires reliable and accurate pH measurement. 10,11 For these reasons we would now recommend the use of a hand-held pH meter in such patients.…”

Novel Cystine Ester Mimics for the Treatment of Cystinuria-induced Urolithiasis in a Knockout Mouse Model

“…At the molecular level, cystinuria is characterized by defective transport of cystine and dibasic amino acids in the kidney and small intestine 7–9 . Cystinuria is an autosomal recessive disorder caused by mutations in either SLC3A1 or SLC7A9 .…”

Early Recognition and Management of Rare Kidney Stone Disorders

“…All patients with APRT deficiency, even if asymptomatic, receive allopurinol therapy because it can prevent stone formation, renal crystal deposition, and the development of kidney failure (Bollée et al, 2012). In patients who do not tolerate allopurinol, febuxostat, another XDH inhibitor, may be an option (Arnadóttir, 2014; Goldfarb, 2011). …”