Cystinuria: an inborn cause of urolithiasis

Eggermann, Thomas; Venghaus, Andreas; Zerres, Klaus

doi:10.1186/1750-1172-7-19

Cited by 94 publications

(110 citation statements)

References 45 publications

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“…Cystine stones can occur at any age. In previous studies, .80% of patients developed their first stones within the first two decades (12), and ,1% of patients with cystinuria had their first stone when .40 years old (6). However, in this cohort, only 30 of 76 (39%) patients had their first stone by the age of 20 years old ( Figure 1A); 16 of 76 (21%) patients did not pass their first stone until they were .40 years old, highlighting the importance of considering this inherited condition as an underlying cause of nephrolithiasis in older age groups.…”

Section: Discussionmentioning

confidence: 96%

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Clinical and Genetic Analysis of Patients with Cystinuria in the United Kingdom

Rhodes

Yarram-Smith²,

Rice

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Cystinuria is a rare inherited renal stone disease. Mutations in the amino acid exchanger System b 0,+ , 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 genotypephenotype 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.

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Section: Discussionmentioning

confidence: 96%

“…Cohorts of patients from Europe, Asia, and North America have been genotyped (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) along with a recently published group of United Kingdom patients (22).…”

Section: Introductionmentioning

confidence: 99%

Clinical and Genetic Analysis of Patients with Cystinuria in the United Kingdom

Rhodes

Yarram-Smith²,

Rice

et al. 2015

Clinical Journal of the American Society of Nephrology

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“…Cystinuria (OMIM 220100), an autosomal recessive hereditary disease, is the most frequent monogenic cause of renal calculi, and is responsible for 1% and 8% of nephrolithiasis in adults and children, respectively (1,2). Cystinuria affects dibasic amino acid and cystine reabsorption in the renal proximal tubule.…”

Section: Introductionmentioning

confidence: 99%

CKD and Its Risk Factors among Patients with Cystinuria

Prot-Bertoye¹,

Lebbah²,

Daudon³

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Cystinuria is an autosomal recessive disorder affecting renal cystine reabsorption; it causes 1% and 8% of stones in adults and children, respectively. This study aimed to determine epidemiologic and clinical characteristics as well as comorbidities among cystinuric patients, focusing on CKD and high BP.Design, setting, participants, & measurements This retrospective study was conducted in France, and involved 47 adult and pediatric nephrology and urology centers from April 2010 to January 2012. Data were collected from 442 cystinuric patients.Results Median age at onset of symptoms was 16.7 (minimum to maximum, 0.3-72.1) years and median diagnosis delay was 1.3 (0-45.7) years. Urinary alkalinization and cystine-binding thiol were prescribed for 88.8% and 52.2% of patients, respectively, and 81.8% had at least one urological procedure. Five patients (1.1%, n=4 men) had to be treated by dialysis at a median age of 35.0 years (11.8-70.7). Among the 314 patients aged $16 years, using the last available plasma creatinine, 22.5% had an eGFR$90 ml/min per 1.73 m 2 (calculated by the Modification of Diet in Renal Disease equation), whereas 50.6%, 15.6%, 7.6%, 2.9%, and 0.6% had an eGFR of 60-89, 45-59, 30-44, 15-29, and ,15, respectively. Among these 314 patients, 28.6% had high BP. In multivariate analysis, CKD was associated with age (odds ratio, 1.05 [95% confidence interval, 1.03 to 1.07]; P,0.001), hypertension (3.30 [1.54 to 7.10]; P=0.002), and severe damage of renal parenchyma defined as a past history of partial or total nephrectomy, a solitary congenital kidney, or at least one kidney with a size ,10 cm in patients aged $16 years (4.39 [2.00 to 9.62]; P,0.001), whereas hypertension was associated with age (1.06 [1.04 to 1.08]; P,0.001), male sex (2.3 [1.3 to 4.1]; P=0.003), and an eGFR,60 ml/min per 1.73 m 2 (2.7 [1.5 to 5.1]; P=0.001).Conclusions CKD and high BP occur frequently in patients with cystinuria and should be routinely screened.

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“…Several mutations on each protein lead to the same phenotype, showing no correlation with the severity of the disease (reference Orphanet: ORPHA214). 2 Simple and effective diagnosis is based on detection of cystine crystals in urine or genotyping; however, there is a need for early markers of tubular injury in order to predict the evolution of the disease and to strengthen the follow-up of patients at higher risk of chronic renal insufficiency. The only available readouts for disease severity are the recurrence of kidney stones, proteinuria, and low estimated glomerular filtration rate (eGFR).…”

Section: ■ Introductionmentioning

confidence: 99%

A New Workflow for Proteomic Analysis of Urinary Exosomes and Assessment in Cystinuria Patients

Bourderioux¹,

Nguyen–Khoa²,

Chhuon³

et al. 2014

J. Proteome Res.

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Cystinuria is a purely renal, rare genetic disease caused by mutations in cystine transporter genes and characterized by defective cystine reabsorption leading to kidney stones. In 14% of cases, patients undergo nephrectomy, but given the difficulty to predict the evolution of the disease, the identification of markers of kidney damage would improve the follow-up of patients with a higher risk. The aim of the present study is to develop a robust, reproducible, and noninvasive methodology for proteomic analysis of urinary exosomes using high resolution mass spectrometry. A clinical pilot study conducted on eight cystinuria patients versus 10 controls highlighted 165 proteins, of which 38 were up-regulated, that separate cystinuria patients from controls and further discriminate between severe and moderate forms of the disease. These proteins include markers of kidney injury, circulating proteins, and a neutrophil signature. Analysis of selected proteins by immunobloting, performed on six additional cystinuria patients, validated the mass spectrometry data. To our knowledge, this is the first successful proteomic study in cystinuria unmasking the potential role of inflammation in this disease. The workflow we have developed is applicable to investigate urinary exosomes in different renal diseases and to search for diagnostic/prognostic markers. Data are available via ProteomeXchange with identifier PXD001430.

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Cystinuria: an inborn cause of urolithiasis

Cited by 94 publications

References 45 publications

Clinical and Genetic Analysis of Patients with Cystinuria in the United Kingdom

Clinical and Genetic Analysis of Patients with Cystinuria in the United Kingdom

CKD and Its Risk Factors among Patients with Cystinuria

A New Workflow for Proteomic Analysis of Urinary Exosomes and Assessment in Cystinuria Patients

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