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PubMed1970

Dipeptide absorption in cystinuria.

Absorption of a dipeptide and its constituent amino-acids has been studied by a perfusion technique in a patient with cystinuria and in a normal subject. Though the cystinuric patient was unable to absorb the dibasic amino-acid lysine in its free form, the dipeptide glycyl-L-lysine was well absorbed. Both free lysine and glycyl-L-lysine were well absorbed in the normal subject.This finding suggests that the reason that clinical malnutrition does not occur in cystinuria, despite defective intestinal absorption and heavy renal loss of dibasic amino-acids and cystine, is that these amino-acids can be absorbed in the form of oligopeptides.

Cystinuria↗
PubMed1978

Erythropoietic protoporphyria, heterozygous cystinuria, and reduced peptidase A activity in a patient with 46,XX/46,XX,18q--mosaicism.

An interesting patient with a deletion of the long arm of chromosome 18 is presented. Her symptoms are severe in comparison with some other 18q--patients, yet she was found to have a mosaicism with a normal 46,XX karyotype in about 20% of her cultured lymphocytes. In addition, she had erythropoietic protoporphyria, was heterozygous for type II or III cystinuria, and had reduced levels of peptidase A activity. Detailed studied on the patient, her family, and two additional 18q--patients suggest that the association with erythropoietic protoporphyria is coincidental and that the cystinuria gene was inherited from the patient's father. The reduced peptidase A activity, however, supports earlier observations that the peptidase A locus maps in the q22 to terminus region of chromosome 18.

Child↗
PubMed1975

Experimental cystinuria: the cycloleucine model. I. Amino acid interactions in renal and intestinal epithelia.

The injection of cycloleucine (1-aminocyclopentanecarboxylic acid (ACPC) into rats produces a hyperexcretion of dibasic amino acids and cystine, an aberration resembling cystinuria. This may constitute a model of experimental cystinuria, and the transport of amino acids involved in this disease was studied with the techniques of everted intestinal sacs (in vitro) and microinjections into renal tubules (in vivo). In verted sacs from normal rats, there was a decrease in transfer and in accumulation of L-cystine (0.03 mM) and L-valine (0.065 mM) when ACPC was on the mucosal (luminal) side. Dibasic amino acids such as L-arginine and L-lysine caused a similar inhibition of the transport of L-cystine. However, when ACPC was on the serosal (antiluminal) side, a lesser effect was noted while arginine and lysine had no effect. Intestinal sacs from treated rats (ACPC, 300 mg/kg X 3 days) transferred and accumulated as much L-cystine as those from control rats. The interaction between cycloleucine and L-cystine was competitive at the luminal and non-competitive at the antiluminal side of the intestine. Cycloleucine inhibited L-lysine transport in a non-competitive fashion at either side of the intestine. L-Lysine also interacted in a non-competitive fashion with L-cystine transport at the luminal membrane. In proximal convoluted tubules, the presence of L-arginine or ACPC caused a decrease in the transport of L-cystine and L-lysine. L-Valine exerted no effect. Furthermore, L-lysine and ACPC did not impair the reabsorption of L-valine significantly. These results suggest a functional heterogeneity between luminal and antiluminal membranes of renal and intestinal epitehlia and the existence, at both membranes, of different transport sites for cystine and dibasic amino acids.

Amino Acids↗
PubMed2005

Giant cystine stone in an infant bladder with no evidence of cystinuria--valence of possible pathomechanisms.

Bladder calculi account for approximately 5% of all urinary calculi. Children are at high risk in endemic areas whereas otherwise the entity is rare. Diet, voiding dysfunction and uncorrected anatomical abnormalities predispose to bladder stone formation. We report the case of a 2-year-old girl with a giant cystine bladder stone without relevant cystinuria and a small left kidney. Suprapubic cystolithotomy was performed for stone removal. We discuss possible associations of cystine calculi with unilateral genitourinary pathologies in the absence of persistent excess cystinuria.

Child, Preschool↗
PubMed1995

Urinary excretion of free cystine and the tiopronin-cysteine-mixed disulfide during long term tiopronin treatment of cystinuria.

We report the results of a biochemical evaluation of long-term treatment of cystinuria with the SH compound tiopronin (2-mercaptopropionylglycine). The effects of tiopronin were studied by monitoring the urinary excretion of free cysteine and the mixed disulfide between tiopronin and cysteine. Thirty-one patients with homozygous cystinuria were treated with tiopronin for 0.4-12 years (mean 7.8 years). The urinary concentration of free cysteine was used to adjust the tiopronin dose. In 28 of the 31 patients a mean urinary cystine concentration of less than 1,200 mumol/1(288 mg/l) was achieved with the final dose. The final daily doses of tiopronin ranged from 250 mg (1.5 mmol) to 3,000 mg (18.4 mmol; mean 1,540 mg; 9.4 mmol). In a majority of the patients the treatment reduced the 24-hour urinary free cystine excretion effectively, on average by 0.61 mumol (0.15 mg)/mg of tiopronin administered. No changes in the efficacy of tiopronin over time were observed, and the frequency of adverse effects was acceptable. To evaluate the effects of tiopronin on the metabolism of cystine we calculated the total urinary excretion of cystine as the sum of free cystine and the amount of cystine corresponding to the cysteine content of the tiopronin-cysteine disulfide. At low doses of tiopronin there was an increase in urinary excretion of the mixed disulfide as well as of total cystine. Monitoring urinary cystine concentration is necessary to achieve adequate individualized doses of tiopronin. Assessment of the mixed tiopronin-cysteine disulfide and the urinary excretion of total cystine shows that tiopronin may interfere with cystine metabolism in a more complex way than through a simple disulfide exchange reaction with urinary cystine.

Adolescent↗
PubMed1995

The effect of sodium intake on cystinuria with and without tiopronin treatment.

As with many other amino acids the transport of cystine across the tubular epithelium is coupled to a parallel transport of sodium. We have studied the effect of a sodium-restricted diet on the urinary excretion of cystine in 13 patients with cystinuria, 7 of whom were treated with the SH compound tiopronin (2-mercaptopropionylglycine). Five of the patients with tiopronin and 5 without were also given sodium bicarbonate. The patients were instructed to follow a sodium-restricted diet during three periods of 2 weeks each. Four levels of sodium intake were obtained including the preexperimental unrestricted diet. The average 24-hour excretion of free cystine increased by 3.1 mumol (0.75 mg) for each millimole increase in urinary sodium (p < 0.001). There was a greater sodium-related increase in excretion of cystine among patients without tiopronin treatment compared with the group with tiopronin (p < 0.01). Withdrawal of sodium bicarbonate resulted in a decrease in the 24-hour cystine excretion (p < 0.05). In the patients treated with tiopronin the excretion of the mixed disulfide increased with increasing urinary sodium (p < 0.05) suggesting a sodium-dependent active tubular reabsorption of this compound as well. We conclude that in spite of a defective proximal tubular reabsorption of cystine in cystinuria the reabsorption can be increased by restricting the intake of sodium. This effect of sodium may have clinical consequences for some cystinuric patients.

Adolescent↗
PubMed1997

Studies on renal function in patients with cystinuria.

Total and separate renal functions were evaluated in 40 patients with cystinuria. The average duration of the renal stone disease was 26 years (range 1-53). The patients had been subjected to a stone-preventing regimen composed of increased fluid intake, urinary alkalinization and treatment with a sulphydryl compound, tiopronin or D-penicillamine, for an average of 11.7 years (range 1-24). Urinary cystine concentration was determined regularly to monitor the treatment. All patients were examined with gamma camera renography and an assessment of glomerular filtration rate (GFR), and early and late renographic results could be compared in 30 patients. The early renographic evaluation showed that 43% of binephric patients (13/30) had an abnormal relative renal function (RRF) before the start of the stone-preventing treatment. At the late evaluation, 50% of binephric patients (17/34) had an abnormal RRF, while 30% of all patients (12/40) had a GFR below the age-related normal range. Thirty percent of 74 evaluated kidneys (22/74) had a separate GFR below an estimated age-related normal range. At the late evaluation only 30% of the patients had functionally unaffected kidneys with both normal GFR and bilateral normal renography. There was, however, no case with terminal renal failure. The separate GFR of kidneys with a history of staghorn stones was significantly lower than for kidneys without that special type of stones, but otherwise there was no relationship between renal functional impairment and other estimates of the activity of the renal stone disease. In conclusion, impairment of renal function is common in patients with stone-forming cystinuria. Stone-preventive treatment appears to be effective in preserving renal function. The high frequency of renal functional impairment justifies close surveillance of this group of patients. By renographic examination, unilateral changes in renal function can be detected at an early stage and patients at risk for further deterioration of renal function can be identified.

Aged↗
PubMed1972

Transport of dibasic amino acids, cystine, and tryptophan by cultured human fibroblasts: absence of a defect in cystinuria and Hartnup disease.

Transport of lysine, arginine, cystine, and tryptophan was studied in cultured skin fibroblasts from normal controls and from patients with cystinuria and Hartnup disease. Each of these amino acids was accumulated against concentration gradients by energy-dependent, saturable mechanisms. Lysine and arginine were each transported by two distinct processes which they shared with each other and with ornithine. In contrast, cystine was taken up by a different transport system with no demonstrable affinity for the dibasic amino acids. The time course and Michaelis-Menten kinetics of lysine and cystine uptake by cells from three cystinuric patients differed in no way from those found in control cells. Similarly, the characteristics of tryptophan uptake by cells from a child with Hartnup disease were identical to those noted in control cells. These findings indicate that the specific transport defects observed in gut and kidney in cystinuria and Hartnup disease are not expressed in cultured human fibroblasts, thus providing additional evidence of the important role that cellular differentiation plays in the regulation of expression of the human genome.

Adult↗
PubMed1990

Diagnostic problems associated with cystinuria.

To elucidate the role of the urinary cystine concentration for the formation of urinary stones, 190 stone-formers were evaluated in this prospective study. Seven patients (3.8%) were heterozygous and one patient (0.5%) was homozygous for cystinuria; only two (1%) of them were cystine stone-formers. Two patients with calcium stones were heterozygous for cystinuria. This study confirms the observation that elevated concentrations of urine cystine are relatively infrequent among patients with urinary stones.

Adult↗
PubMed1977

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.

Adult↗
PubMed1977

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.

Adult↗
PubMed1975

Jejunal and ileal absorption of dibasic amino acids and an arginine-containing dipeptide in cystinuria.

Ileal transport of dibasic amino acids has not previously been studied in the intestine of healthy volunteers or cystinuric patients. Experiments have therefore been designed to compare ileal and jejunal absorption of lysine and arginine both in normal subjects and cystinuric patients. In addition, jejunal perfusion experiments have been carried out to investigate absorption of the dipeptide L-arginyl-L-leucine. The results indicate that, at the concentrations studied (4.2 mM lysine, 1 mM arginine), severe transport defects exist throughout the whole small intestine for both amino acids in cystinuria. Despite the transport defect for free arginine, cystinuric patients absorbed the dipeptide L-arginyl-L-leucine normally. Because of the transport defect for free arginine, it has been possible to show that during absorption of L-arginyl-L-leucine in cystinuria approximately 30% of dipeptide-bound arginine can be recovered from the gut lumen in the free form. These findings indicate that the prime function of specific amino acid transport systems during the absorption of protein digestion products may be as a "recapture mechanism" for amino acids liberated as a result of mucosal cell peptide hydrolysis.

Adult↗
PubMed2002

The impact of cystinuria on renal function.

PURPOSE: Patients with cystinuria frequently have recurrent renal calculi and may subsequently require multiple stone removing procedures during their lifetime which could have an impact on overall renal function. We determined the potential impact of cystinuria and cystine stone formation on the level of renal function compared to calcium oxalate stone formers. MATERIALS AND METHODS: Clinical data on 40 cystinuric patients followed at 2 medical centers and 45 such individuals in a large stone population data base were analyzed. These results were compared to data on 3,964 calcium oxalate stone formers enrolled in this data base. RESULTS: Mean serum creatinine plus or minus standard deviation for stone forming cystinuric patients was significantly higher than that of the calcium oxalate cohort (1.13 +/- 0.28 versus 1.01 +/- 0.28 mg./100 ml., p = 0.0001). A significantly greater percentage of cystinuric patients (5.8%) had an abnormally increased serum creatinine compared to the calcium oxalate stone formers (2.2%, p = 0.046). Male gender, increasing number of open surgical stone removing procedures and nephrectomy were significant variables associated with an increased serum creatinine (p = 0.0010, p = 0.0038, p = 0.0133, respectively). An increasing number of open surgical stone removing procedures had a significant positive correlation with performance of nephrectomy in the cystinuric population (p = 0.0166). A significantly greater percentage of cystinuric patients compared to the calcium oxalate cohort were subjected to nephrectomy (14.1% versus 2.9%, p = 0.007). CONCLUSIONS: Cystinuric patients have higher serum creatinine levels than calcium oxalate stone formers and they are at more risk for renal loss. When stone removal is required, a minimally invasive approach is preferred.

Adolescent↗
PubMed2002

Cystinuria: cause of recurrent renal stones in a 4-year-old girl.

This paper presents the case report of a 4-year and 6-month old girl with cystinuria. She clinically presented with recurrent radiopaque renal stones since the age of 3 years. She received 2 subsequent operations of pyelolithotomy combined with ureterolithotomy at the age of 3 years 6 months, and pyelolithotomy alone at the age of 5 years. She was initially diagnosed as having cystinuria by the presence of hexagonal plate crystals in her acidified urine and positive for the urinary cyanide-nitroprusside test. The diagnosis was confirmed by urinary amino acid analysis using quantitative ion-exchange chromatography which revealed increased amounts of cystine and dibasic amino acids of lysine and ornithine. In spite of maintaining a high fluid intake and alkalinizing urine by giving potassium citrate after the first operation, recurrent renal stones were found. Therefore, after the second operation, D-penicillamine was additionally introduced. During the 18-month follow-up, although there were recurrent renal stones, the rate of stone formation was slower. To the authors' knowledge, this is the first case report in Thailand.

Child, Preschool↗
PubMed2003

[Cystinuria update: clinical, biochemical and genetic aspects].

Cystinuria is an autosomal recessive disorder with an estimated incidence of 1 case in 7000 live births, that results in elevated urinary excretion of cystine and dibasic aminoacids: ornithine, lysine and arginine. Discussed by Sir Archibald Edward Garrod, in 1908, as one of the four first known inborn errors of metabolism, it is characterized by a defect in transport of cystine and dibasic aminoacids, that affects their reabsortion in both renal tubule and gastrointestinal tract. To date, according to the recent molecular findings, two genes have been identified as responsible for this disease: SLC3A1 and SLC7A9. A more accurate pheno/genotyping identification of cystinuric patients will allow to improve prophilaxis and therapy for this illness. Cystinuria only causes recurrent urolithiasis (about 1-2 / of renal calculi in adults) and its associated complications as clinical feature because of poor cystine solubility at low pH. An accurate control over prohylaxis (based on high water intake and potassium citrate treatment, on first line, and tiol-derivatives treatment, on second line) must be taken in patients -like homozygous type I- with high lithiasis risk. However, approximately one half of patients under prophylaxis control will develop recurrent lithiasis; in this case, only urology or surgical approaches would be possible. 474 Updated knowledge about biochemical, genetic, clinical, diagnosis, prevention, treatment and prognosis aspects of this, relatively unusual, disease has been reviewed in this article.

Amino Acid Transport Systems, Basic↗
PubMedDate not supplied

Captopril therapy of recurrent nephrolithiasis in a child with cystinuria.

Traditional and current therapies for cystinuria have been difficult for patients, only partially effective, or associated with substantial risk of serious side effects. We present a case of cystinuria that has been managed for 1 year on captopril, with elimination of recurrent nephrolithiasis and with no observable morbidity.

Adolescent↗
PubMed1987

Management of the patient with cystinuria.

Cystinuria is a complex hereditary disorder characterized by excessive urinary excretion of cystine. For the homozygote patient who excretes more than 400 mg per day, recurrent urinary calculus formation can necessitate repeat surgical manipulation with its associated morbidity. This review details the long-term medical management program for the patient with cystinuria and recurrent calculus formation.

Adult↗
PubMed1979

[The hyperaminoacidurias with special reference to cystinuria].

Increased urinary excretion of free amino acids is a sign which requires determination of the underlying cause. Physiological aspects of tubular transport with emphasis on the role played by transport proteins or carriers are briefly discussed. Subsequently we present a resumptive classification. In prerenal hyperaminoaciduria the urinary excretion of amino acids just reflects the error in amino acid metabolism. Depending on tubular reabsorption of the amino acid involved in the metabolic error three types can be distinguished: the overflow, the competitive and the non-threshold hyperaminoacidurias. Renal hyperaminoaciduria can either be specific for individual or group-related amino acids, or generalized involving all amino acids. With the exception of classical cystinuria the various hyperaminoacidurias have more theoretical than clinical importance. Generalized hyperaminoaciduria is always a symptom of severe tubular disturbance which can be produced by various metabolic diseases, intoxications or deficiency states. Finally we present our experience in the treatment of cystinuria with mercaptopropionyl-glycine.

Amino Acids↗