BACKGROUND AND OBJECTIVES: Cystinuria is a rare inherited renal stone disease.
Mutations in the amino acid exchanger System b0,+, the two subunits of which are encoded by SLC3A1 and SLC7A9, predominantly underlie this disease. The work analyzed the epidemiology of cystinuria and the influence of mutations in these two genes on disease severity in a United Kingdom cohort.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Prevalent patients were studied from 2012 to 2014 in the northeast and southwest of the United Kingdom. Clinical phenotypes were defined, and genetic analysis of SLC3A1 and SLC7A9 combining Sanger sequencing and multiplex ligation probe-dependent amplification was performed.
RESULTS: In total, 76 patients (42 men and 34 women) were studied. All subjects had proven cystine stones. Median age of presentation (first stone episode) was 24 years old, but 21% of patients presented after 40 years old. Patients had varied clinical courses, with 37% of patients having ≥10 stone episodes; 70% had evidence of CKD, and 9% had reached ESRD as a result of cystinuria and its complications. Patients with cystinuria received a variety of different therapies, with no obvious treatment consensus. Notably, 20% of patients had staghorn calculi, with associated impaired renal function in 80% of these patients. Genetic analysis revealed that biallelic mutations were present in either SLC3A1 (n=27) or SLC7A9 (n=20); 22 patients had only one mutated allele detected (SLC3A1 in five patients and SLC7A9 in 17 patients). In total, 37 different mutant variant alleles were identified, including 12 novel mutations; 22% of mutations were caused by large gene rearrangements. No genotype-phenotype association was detected in this cohort.
CONCLUSIONS: Patients with cystinuria in the United Kingdom often present atypically with staghorn calculi at ≥40 years old and commonly develop significant renal impairment. There is no association of clinical course with genotype. Treatments directed toward reducing stone burden need to be rationalized and developed to optimize patient care.
Written by:
Rhodes HL, Yarram-Smith L, Rice SJ, Tabaksert A, Edwards N, Hartley A, Woodward MN, Smithson SL, Tomson C, Welsh GI, Williams M, Thwaites DT, Sayer JA, Coward RJ. Are you the author?
Academic and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; Bristol Genetics Laboratory-Pathology Sciences; Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Department of Urology, National Health Service Foundation Trust, Newcastle upon Tyne, United Kingdom; Department of Clinical Genetics, University Hospitals, Bristol, United Kingdom; Richard Bright Renal Unit, Southmead Hospital, Bristol, United Kingdom; Department of Renal Medicine, Freeman Hospital, Newcastle upon Tyne, United Kingdom; Institute of Genetic Medicine, International Centre for Life and Department of Renal Medicine, Freeman Hospital, Newcastle upon Tyne, United Kingdom.
Reference: Clin J Am Soc Nephrol. 2015 May 11. pii: CJN.10981114.
doi: 10.2215/CJN.10981114
PubMed Abstract
PMID: 25964309