**7.1. Fluid**

[13] and 2p21 deletion syndrome [4]. Each of these syndromes includes the homozygous disruption of the *SLC3A1* gene, and therefore produce cystinuria type AA as part of their

72 Updates and Advances in Nephrolithiasis - Pathophysiology, Genetics, and Treatment Modalities

Hypotonia-cystinuria syndrome arises from homozygous deletion of two genes, *SLC3A1* and *PREPL*, and has the least severe phenotype. The main phenotypical features are infantile hypotonia, poor sucking and associated feeding problems, growth hormone deficiency leading to growth restriction, mild facial dysmorphic features and cystinuria type AA [12]. Atypical hypotonia-cystinuria syndrome, which features disruption to three contiguous genes, *SLC3A1*, *PREPL* and *C2orf34*, produces an intermediate phenotype featuring mild to moderate intellectual disability in addition to the features of hypotonia-cystinuria syndrome [13]. The 2p21 deletion syndrome, resulting from homozygous loss of four contiguous genes, *SLC3A1*, *PREPL*, *C2orf34* and *PPM1B*, produces a more severe phenotype, as expected, owing to the higher number of genes affected [4]. Patients with 2p21 deletion syndrome may have neonatal seizures, severe developmental delay and lactic acidosis in addition to the typical

Confirmation of significantly elevated urinary cystine levels is key to establishing a diagnosis of cystinuria. The cyanide-nitroprusside test is a qualitative test traditionally used as a screening test for cystinuria; a positive result occurs when the urine turns red after the addition of the reagent, indicating a urinary cystine level >75 mg/g creatinine [2]. However, as the cyanidenitroprusside test is designed to detect amino acids containing a free sulfhydryl or disulphide bond there is the possibility of obtaining a false positive result in cases of homocystinuria and acetonuria [4]. Precise quantitative measurement of urinary cystine levels is therefore always indicated in cystinuria patients, and homozygotes will often have grossly elevated levels of >300–400 mg/L, compared to the normal level of 30 mg/L [4]. In addition to measuring urinary cystine levels by mass spectrometry, urine microscopy may also be performed to look for the

Cystinuria is an inherited metabolic disorder requiring lifelong treatment. In the absence of any specific treatment to reverse the abnormal dibasic amino acid transport, the target of therapy is to prevent cystine stone formation and thereby minimise complications of recurrent nephrolithiasis. Management of patients should ideally be undertaken in dedicated metabolic stone clinics [14]. Initial treatment is focussed on increased fluid intake, dietary modification and urinary alkalisation, but these interventions are cumbersome and patient compliance often limits their effectiveness. In refractory cases, a cystine-binding drug may be added to the treatment regime, although continued adherence to the initial conservative treatments is crucial for successful outcomes. Surgical intervention is reserved for large or symptomatic

features associated with hypotonia-cystinuria syndrome (**Table 1**).

hexagonal colourless crystals which are pathognomonic for cystinuria [4].

calculi which are causing obstruction, infection or pain.

**6. Biochemistry and urine analysis**

**7. Treatment of cystinuria**

clinical phenotype.

Maintaining a high fluid intake, aiming to produce at least three litres of urine per day, is the cornerstone of successful cystinuria treatment. Establishing a hyperdiuresis reduces the cystine concentration in the urine, thereby reducing the risk of nephrolithiasis [4]. The therapeutic target is to keep urinary cystine levels below 300 mg/L [15]. Nocturnal intake of fluid, both before bed and ideally at least once overnight, is an important factor, in order to avoid the increased risk of stone formation associated with the body's natural tendency to concentrate urine overnight [16]. However, it is hard for patients to comply with long-term [15]. Continued high fluid intake is a crucial factor in determining treatment success in cystinuria, both in isolation and in patients also taking thiol-binding drugs [15]; patient education regarding this is essential to achieve compliance with this burdensome intervention.
