**2. Diagnosis of cystinuria: historical and modern**

Cystinuria may present with renal calculi at any age, but most patients will present before 30 years of age. Historically, cystinuria was diagnosed mainly through renal calculi analysis and this lead to an underestimation of the incidence of the condition [1]. As methods developed to analyse the cystine concentration in urine samples it became possible to detect cases with confirmed accuracy, and also provided a valuable screening tool. The cyanide-nitroprusside reaction, developed by Brand et al. in 1930, provided a qualitative method of measuring excessive urinary excretion of cystine [1]. This test is positive when the urinary cystine level is greater than 75 mg/g creatinine [2].

Modern diagnostic methods may utilise a combination of laboratory tests, stone composition analysis, radiological investigation and genetic testing. Urinary cystine levels may be precisely measured using mass spectrometry, and are significantly elevated in cystinuria patients [4]. Levels of urinary cystine has also been used historically to detect carrier status, but a molecular genetic diagnosis is more reliable in the modern era. On urine microscopy, hexagonal crystals can be visualised which are pathognomonic [3]. Cystine stones are faintly radioopaque and have a homogenous, ground-glass appearance [4], but may be missed on plain X-ray imaging. Cystine stones are often 100% cysteine but may contain variable amounts of calcium. CT-scanning allows accurate detection and localisation of cystine stones within the kidney and urinary tract.
