Diagnosis Of Cystinuria Research Articles

Staghorn cystine stone in a 72-year-old recurrent calcium stone former

This case deals with the first diagnosis of Type B cystinuria with cystine nephrolithiasis in a 72-year-old male. Cystinuria is an inherited disease that consists of congenital abnormalities of renal and intestinal transport of dibasic amino acids. It often leads to frequent recurrent stone formation. Cystine stones most frequently occur in the 1st through 3rd decades of life with a decreased incidence in old age. This case shows that the first diagnosis of cystinuria may be made even in the 8th decade, without any family history, and in a patient with a history of recurrent calcium stone disease. Therefore, the chance of cystinuria must be always considered, even in older calcium stone formers.

1843 MANAGEMENT OF CYSTINURIC PATIENTS IN A DEDICATED STONE CLINIC DECREASES STONE EVENTS

You have accessJournal of UrologyStone Disease: New Technology/SWL, Ureteroscopic or Percutaneous Stone Removal III1 Apr 20121843 MANAGEMENT OF CYSTINURIC PATIENTS IN A DEDICATED STONE CLINIC DECREASES STONE EVENTS Jacob Cohen, Leonard Glickman, David Goldfarb, and Michael Grasso Jacob CohenJacob Cohen New York City, NY More articles by this author , Leonard GlickmanLeonard Glickman New York City, NY More articles by this author , David GoldfarbDavid Goldfarb New York City, NY More articles by this author , and Michael GrassoMichael Grasso Valhalla, NY More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1931AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Patients with cystinuria frequently undergo multiple surgical procedures throughout their lifetime, with potential loss of renal function and attendant morbidity. We investigate whether referral to a dedicated stone clinic, with emphasis on minimizing surgical morbidity, and comprehensive dietary and medical therapy, can decrease stone events and preserve renal function. METHODS We retrospectively reviewed the records of 41 consecutive cystinuric patients treated over a 12-year time period. Patients were followed semiannually with renal sonograms, 24-hour urine collections and clinic visits with an endourologist and nephrologist with a special interest in treating cystinuria. Surgical intervention, when indicated, utilized flexible ureteropyeloscopy preferentially to percutaneous procedures, except for complete staghorn or infectious calculi. Stone-free status was defined as absence of stones or asymptomatic stones up to 4 mm on post-procedural sonography, and stability of disease was defined as having achieved stone free status or maintaining stable, asymptomatic renal stones at last follow-up. RESULTS Our 41 patients had a mean age of diagnosis of cystinuria of 21 years (range 4 to 44). At referral, 6 (15%) patients had a nonfunctioning or surgically absent kidney as a result of prior procedures. During mean 67 month follow-up (range 1 to 172), our patients underwent 101 procedures for 80 stone events, 15 of which were for bilateral stones. Under our care, operative interventions were more likely to consist of ureteroscopy (used in 76% of patients), as opposed to percutaneous procedures (used in 24%). Our patients experienced decreased frequency of stone events and subsequent surgical procedures, undergoing one surgery every 38 months as opposed to every 27 months prior to referral. Mean stone size was 34 mm (range 20 to 70 mm), and we achieved overall stone clearance of 84%, with no difference noted between ureteroscopy or percutaneous procedures (Table 1). Renal function remained stable during follow-up, and stability of disease was achieved in 36 (88%) of patients. Table 1. Stone free rate by procedure No.(%) Meanstone size(mm) Stonefree(%) Overallproceduresperformed 101 34 84 Ureteroscopy 77(76) 21 83 Staged 24(24) Bilateral 10(10) PCNL⁎ 24(24) 35 85 Staged 9(9) Bilateral 5(5) ⁎ PCNL = percutaneous nephrostolithotomy CONCLUSIONS For cystinuric patients, a dedicated stone clinic emphasizing careful surveillance, medical management, and surgical intervention minimizing renal trauma effectively reduces stone events and their associated morbidity. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e745 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jacob Cohen New York City, NY More articles by this author Leonard Glickman New York City, NY More articles by this author David Goldfarb New York City, NY More articles by this author Michael Grasso Valhalla, NY More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

New horizons in the management of patients with cystinuria

Although the formation of cystine stones is seen in only a small fraction of all patients with urolithiasis, this disease is associated with a pronounced morbidity. The difficult clinical management of these patients, with the aim of arresting or decreasing the rate of recurrent stone formation, is well recognized. This review summarizes some recent knowledge. An early and correct diagnosis of cystinuria is fundamental for a successful course of the disease in these patients. Formation starts early in life, and attention to this diagnosis is necessary for the paediatric stone formers. New radiological and biochemical improvements seem useful in this respect. A combination of medical tools is usually necessary to influence the very often, troublesome stone-forming activity. Urine dilution, alkalization and chelating therapy have remained the cornerstones of the therapeutic approach. The importance of a high urine pH has been further emphasized, and the possibility to use acetazolamide is a promising improvement of the medical treatment. In order to increase the compliance and reduce the need of active stone removal, special stone clinics seem to be of particular value. The understanding of the genetic background might open future treatment alternatives. Patients afflicted by cystine stone disease need an aggressive medical treatment, gentle stone-removing surgery and careful follow-up.

LC‐MS/MS determination of dibasic amino acids for the diagnosis of cystinuria. Application in a family affected by a novel splice‐acceptor site mutation in the SLC7A9 gene

Cystinuria is an autosomal recessive disorder caused by defective transport of cystine and the dibasic amino acids ornithine, lysine and arginine across cell membranes. Poor solubility of cystine in urine leads to kidney stones and associated symptoms and complications. Mutations of genes SLC3A1 and SLC7A9 encoding for amino acid transport systems are responsible for different types of cystinuria. In this study we describe a new LC-MS/MS assay for these amino acids in urine. Moreover, we report a novel splice-acceptor site mutation in the SLC7A9 gene that we believe is the cause of the phenotype observed in four siblings from a first-cousin marriage. Into the wells of a 96-well microtitre plate, 10 microl of urine was mixed with 90 microl of a solution containing [(2)H4]cystine, [(2)H2]ornithine, [(13)C,(2)H4]arginine and [(2)H5]glutamine that was used as an internal standard for lysine. Chromatographic separation was achieved isocratically and detection was in the selected-reaction monitoring mode. The injection-to-injection time was 8 min. Calibration curves were linear up to 1000 micromol/L. Intra-day (n = 10) and inter-day (n = 6) variations (750 and 10 micromol/L) were less than 11.4%. Urine samples from healthy individuals (n = 135) were analysed and age-matched reference ranges were generated. The method was applied retrospectively and prospectively to analyse samples (n = 13) from nine cystinuria patients. The mutation reported here was not found in 100 controls with similar ethnicity to the studied family and is believed to have consequences for the transcribed mature RNA and protein structure and function.

Urine sediment from a Chihuahua

A 6-year-old, intact male Chihuahua was presented with stranguria and painful urination of 5 days duration. Cystine crystals were observed in low numbers in unstained urine sediment preparations, and a diagnosis of cystinuria was made. Uroliths were removed surgically from the urethra and the bladder, and mineral analysis indicated the stones were composed of 100% cystine. Cystinuria results from an inherited defect in renal tubular transport of cystine that affects many breeds and has been found as an autosomal recessive trait in Newfoundlands. Accurate identification of cystine crystals in urine is an important means of diagnosing cystinuria.

Sensibilidad, especificidad y valor predictivo del análisis genético de variantes en el gen SLC3A1 aplicado al diagnóstico de cistinuria en población española

To test the clinical usefulness of the analysis of point mutations R452W, M467T, 114C > A, 231T > A, 1136 + 3delT and 1332 + 7T > C in the gene SLC3A1 as well as their possible haplotypes used for the diagnosis of cystinuria in the mediterranean spanish population.A total of 48 patients with cystinuria, 44 relatives without cystinuria, and 81 healthy controls were studied. A genetic analysis was conducted in order to identify variants in the gene SLC3A1. The sensitivity, specificity, and predictive value for each genetic variant and for the possible haplotypes were calculated.The specificity of mutations M467T, R452W, and 231T > A used for the diagnosis of cystinuria in the general population or for the different subtypes of cystinuria in involved families, was higher than 90%; nevertheless, none of the analysed variants reached a sensitivity higher than 80%. In the study of haplotypes, the highest sensitivity was obtained with the haplotype CTTT (83.8%); however, its specificity and predictive value were low (20.6% and 53.4%, respectively).The studied genetic variants did not show enough clinical usefulness.

Mutations in the SLC3A1 gene in cystinuric patients: frequencies and identification of a novel mutation.

Cystinuria is a frequent autosomal recessive transport disorder characterized by defective renal resorption of cystine and other dibasic amino acids. Biochemically, three types of cystinuria can be defined. Here we present our results of screening for mutations in the SLC3A1 gene, which codes for a dibasic amino acid transporter protein and appears to be involved in the pathogenesis of cystinuria type I. Our study population consists of 5 Italian cystinuria type I patients and 10 cystinuric patients as yet unclassified as to clinical type. The latter were of different ethnic origin. In total, we found 13 point mutations and 8 genomic rearrangements in 15 cystinuric patients, i.e., our detection rate was 70% (23/30 chromosomes). Remarkably, in patients known to be suffering from cystinuria type I, the mutation detection rate was only 50%, whereas in patients unselected as to cystinuria type, we found 80% of mutations. Additionally, our results, as with those published in the literature, indicate a possible population specific distribution of mutations: Each of the 4 Greek patients analyzed here showed homozygosity for mutation T216M in exon 3. Analysis of a Yugoslavian patient showed homozygosity for a novel mutation, R365L, in exon 6 (nt1094G > T). Findings from molecular genetic studies, as well as physiological investigations, suggest that there are further genes that play a role in the etiology of cystinuria. Nevertheless, our results show that screening for mutations in the SLC3A1 gene can be a meaningful step toward molecular genetic diagnosis of cystinuria in patients without biochemical classification. As with cystic fibrosis, the finding of specific mutations in particular ethnic populations, suggest that the diagnostic approach should take into consideration a patient's ethnic origins.

Urinary excretion of amino acids in normal and cystinuric dogs

The 24-h urine excretion of 20 amino acids was investigated in 24 cystinuric and 15 normal dogs. The diagnosis of cystinuria was based on infrared spectroscopy of removed uroliths, which in all cases were composed of pure cystine. Seven of 24 cystinuric dogs showed normal cystine excretion compared to normal dogs, and four of 24 dogs showed normal total amino acid excretion. In contrast to earlier investigations, almost half of the cystinuric dogs (46%) showed elevated excretion of five or more amino acids. Isolated cystinuria, or isolated dibasic amino aciduria was not found. Compared to normal dogs, the cystinuric dogs showed a significantly (P < 0.05) increased excretion of cystine, arginine, lysine, cystathionine, glutamic acid, threonine and glutamine. There was a significant correlation (P < 0.05) between the urinary excretion of cystine and 10 other amino acids, with the highest correlation found (P < 0.001) for arginine, lysine, cystathionine, ornithine and 1-methyl-histidine. Three patterns of amino acid excretion could be identified: (1) increased excretion and a significant correlation with cystine for the three dibasic amino acids (lysine, arginine and ornithine), compatible with a common reabsorption mechanism as shown in man. This pattern was also found for cystathionine and glutamic acid, which might indicate a relation in metabolism or transport; (2) increased excretion but no correlation with cystine for glutamine, threonine and citrulline; (3) good correlation with cystine, but no increased excretion for 1-methyl-histidine, phenylalanine, 3-methyl-histidine, leucine and alanine. The great variation in urinary cystine excretion suggests that factors other than the excretion of cystine must be considered as causes of cystine urolith formation. For example, cystinuric dogs were found to have lower diuresis than normal dogs and produced urine with higher cystine concentration thereby increasing the risk of cystine urolith formation.

Cystine Stones: The Impact of New Treatment

The hardness and frequent recurrence of cystine stones present a special challenge to the urologist. In this study, 15 cystinuric patients (11 males, 4 females; mean age 36 years, range 17-54) were treated and followed up over a period of 30 months (range 2-40). Most patients had previous history of open surgery. The diagnosis of cystinuria was confirmed by metabolic studies and infrared spectrometry of stones. Over the follow-up period recurrence was observed in 23 instances in 11 patients, leading to 38 "stone treatments" on 74 cystine stones. The percutaneous approach was used alone in 9 cases and in association with extracorporeal shock wave lithotripsy (ESWL) in 9 cases. ESWL was used alone in 18 cases. Medical treatment included high fluid intake, alkalinisation and Thiola (tiopronin, N-(2-mercaptopropionyl)glycine) in 6 patients. The overall stone-free rate assessed 3 months after treatment was 44.7%, which compares poorly with the rate for non-cystine stones. The recurrence rate is very high and instrumental treatment should not therefore be used excessively; it is indicated only for stones that are symptomatic or refractory to intensive medical therapy.

Investigations on the early diagnosis of cystinuria in children.

The procedure described confirms that the Ni2+/S2O4(2-) tablet test is a suitable quick cystine screening test for large groups. In 16 (0.67%) of 2,395 one- to three-year-old crèche children significantly enhanced cystine levels of 0.60-0.96 mmol/l were found. The corresponding creatinine values (mmol/l) did not reveal any significant deviations from the normal values. In a preliminary group of 9 children, enhanced lysine levels support the suspicion of the existence of cystinuria without clinical symptoms. This also forms the basis for further necessary family histories as well as for prophylactic measures.

Cystine stones

We report on 9 patients, 5 men and 4 women, with cystine stones. Eight were seen previously at other hospitals, and a total of 18 operations were performed for stones before the diagnosis of cystinuria was made and medical treatment instituted. The pathogenesis and rationale for medical treatment is reviewed, and the need for early diagnosis is emphasized.

Poor diagnosis of cystinuria in New South Wales.

The case histories of 33 stone-forming cystinurics were analysed with respected to the time taken for the diagnosis of cystinuria to be made. Stone analysis showed that 17 patients were diagnosed at the time of first stone formation, but the other 16 patients were not diagnosed until they had suffered repeated episodes of calculi. There were 25 episodes of renal colic in 14 patients before any stone formation, and there was no case of cystinuria diagnosed as the result of a search for the cause of the renal colic.

Evaluation of the nitroprusside test for the diagnosis of cystinuria.

Because of the wide acceptability of the nitroprusside test for the diagnosis of cystinuria, an analysis of 525 consecutive urine tests performed at this laboratory was undertaken, the nitroprusside test result being correlated with the urinary cystine excretion as determined by paper chromatography, high-voltage electrophoresis and chemical tests. It was found that the nitroprusside test clearly separated urine samples into categories of cystine excretion within the normal, heterozygote and homozygote range (P less than 0-001). However, 7 (1-33%) urine specimens from homozygous cystinurics gave a negative nitroprusside result. If properly performed on a concentrated urine specimen, this test is a very accurate means of diagnosing cystinuria (expected error approximately 1%), but it is not infallible.

The New South Wales register of cystinurics: first report January to December, 1971.

To test the validity of the presymptomatic diagnosis of cystinuria and to learn more of the long term history of the condition and the value of prophylactic treatment, a register of known symptomatic cystinurics and presymptomatic cysti- nurics has been established. It is hoped to maintain a long-term follow up of these patients. One hundred and one known homozygous cystinurics have been registered. The high morbidity of the condition is exemplified by the histories of the known stone-forming individuals.

Cystinuria, hyperuricemia and uric acid nephrolithiasis. Case report.

A patient was reported who illustrates the importance of early diagnosis of cystinuria. Hyperuricemia and uric acid lithiasis also were present. This association with cystinuria has been reported prev