sodium-bicarbonate and Cystinuria

Cystinuria is a relatively uncommon cause of pediatric stone disease, but has significant morbidity if not properly controlled because of its significant stone recurrence rate. Cystinuria is caused by the inability of the renal tubules to reabsorb filtered cystine, which is poorly soluble at a typical urine pH <7. Although many advances have been made in the understanding of the genetic and physiological basis of cystinuria, the cornerstones of treatment still involve stone prevention with dietary measures and pharmacological therapy, coupled with surgical interventions for stone removal. Pharmacological treatments can carry significant side effects that must be monitored and can limit therapy as well as impede compliance. Most patients will require surgical intervention for stone removal, although compliance with prevention strategies reduces the need for intervention.

Topics: Absorption; Animals; Cystine; Cystinuria; Diet, Protein-Restricted; Diet, Sodium-Restricted; Genetic Predisposition to Disease; Humans; Hydrogen-Ion Concentration; Kidney Tubules; Nephrolithiasis; Patient Compliance; Phenotype; Potassium Citrate; Sodium Bicarbonate; Solubility; Sulfhydryl Compounds; Treatment Outcome; Urologic Surgical Procedures

The final phenotype of patients with cystinuria depends on the absence or molecular defect, more or less acute, of the transport of cystine and dibasic aminoacids, and, also on environmental factors. The objective of this work is to study the effect of the modulation of some environmental factors (urinary pH, intake of liquids, pharmacological treatment and, specially, diet) on the final phenotype of the patient with cystinuria.. We study 45 patients with cystinuria (25 men and 20 women), 42 relatives (15 men and 27 women) and 90 unrelated controls. Anthropometric, clinical (personal and familiar history of urinary infections, colics and calculi expulsion), biochemical (microscopy analysis of urine and urinary aminoacids cuantification) and life style (diet and medical treatment) variables were obtained. Statistical analysis was performed using tests to compare means and frequencies and, also, logistic regression and multivariate analysis.. Of the 45 patients with cystinuria, only 20% showed cystine cristalls in urine, the rest of the phenotypical manifestations of cystinuria were found with the same prevalence as in relatives and in the control group. 50% of the patients did not undergo any therapeutic intervention; of these, only 50% were effective. In patients with cystinuria, the presence of cystine cristalls was associated with a diet rich in meats and poor in milk products (p < 0.05). Meat consumption also tend to associate with a higher risk of urinary infections, meanwhile the stone expulsion showed a negative tendance with a diet rich in phytate. The elevate consumption of oranges and mandarins was the variable of the diet which was more associated with urinary aminoacids concentrations, specially with lower levels of lysine and arginine (p < 0.05).. Some components of the diet, in addition to standard treatment, modulate the phenotypical manifestations of cystinuria.

Topics: Adolescent; Adult; Amino Acids; Child; Citrus sinensis; Combined Modality Therapy; Cystine; Cystinuria; Dairy Products; Female; Fluid Therapy; Humans; Hydrogen-Ion Concentration; Life Style; Male; Meat; Middle Aged; Phenotype; Potassium Citrate; Sodium Bicarbonate; Surveys and Questionnaires; Urine; Urolithiasis

Medical treatment of cystinuria is often disappointing. Patients undergo frequent surgery, which is often followed by early relapse. The aim of our study was to evaluate the efficacy of medical treatment of cystinuria, to prevent formation or to reduce the numbers and dimensions of renal stones. Twenty cystinuric patients were treated with a combined approach, including cystine-binding drugs. Free and bound urine cystine levels were measured every 4 months. Drug dosage was adjusted to maintain free urine cystine level below 100 micromol/mmol creatinine. Eighteen patients completed the study; detection of new stones was reduced from 0.28 per year to 0.03 per year, and, in six patients, the numbers and dimensions of pre-existing renal stones were reduced. Surgery was required in one subject, and no relapse was observed 12 months afterwards. The dosage required to achieve target levels was closely correlated with patient body weight: older children required a lower dose. Medical management of cystinuria is feasible. The treatment must be personalised in children, as the amount of drug required is strictly dependent on body size.

Topics: Adolescent; Adult; Alkalies; Chelating Agents; Child; Child, Preschool; Cystine; Cystinuria; Diuretics; Drug Monitoring; Humans; Infant; Penicillamine; Potassium Citrate; Prospective Studies; Sodium Bicarbonate; Tiopronin; Urinary Calculi

For many years, urine alkalinization has been one of the cornerstones in the treatment of homozygous cystinuria. Because of the relationship found between the excretion of urinary sodium and cystine, potassium citrate has emerged as the preferred sodium-free alkalizing agent. To evaluate the usefulness of potassium citrate for urine alkalization in cystinuric patients, sodium bicarbonate and potassium citrate were compared in 14 patients (10 on tiopronin treatment and four without treatment with sulfhydryl compounds). The study started with 1 week without the use of any alkalizing agents (Period 0) followed by 2 weeks with sodium bicarbonate (Period 1) and 2 weeks with potassium citrate (Period 2). Urinary pH, volume, excretion of sodium, potassium, citrate and free cystine, as well as the plasma potassium concentration, were recorded. Potassium citrate was shown to be effective as an alkalizing agent and, in this respect, not significantly different from sodium bicarbonate. Even though a normal diet was used, a significant increase in urinary sodium excretion was observed with sodium bicarbonate (Period 1). Urinary potassium and citrate excretion increased with potassium citrate (Period 2). A significant correlation was found between urinary sodium and cystine in the tio-pronin-treated patients. No significant differences in cystine excretion were recorded in Periods 0, 1 and 2. Plasma potassium was significantly higher during Period 2, but only one patient developed a mild hyperkalemia (5.0 mmol/l). The use of potassium citrate for urine alkalization in homozygous cystinuria is effective and can be recommended in the absence of severe renal impairment.

Topics: Adult; Aged; Alkalies; Cystinuria; Female; Homozygote; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Natriuresis; Potassium; Potassium Citrate; Sodium Bicarbonate; Tiopronin

We determined the efficacy of a contemporary medical regimen for treatment of cystinuria.. A total of 16 patients with cystinuria was followed for 7 to 141 months (mean 78.1). Standard therapy included hydration and alkalization. D-penicillamine or alpha-mercaptoproprionylglycine was added for failure of hydration and alkalization to prevent new stones or stone growth, or to cause dissolution. Captopril was added for failure of or intolerance to D-penicillamine or alpha-mercaptopropionylglycine. Radiography was performed every 6 to 12 months, at which time stone events were documented.. During hydration and alkalization 46 stone events occurred in 8 of 9 patients (1.6 events per patient-year). With addition of thiol derivatives 7 of 9 patients experienced 24 stone events, all 6 treated with hydration, alkalization and captopril experienced 10 events, and 4 of 5 treated with alkalization, thiols and captopril experienced 8 events (0.52, 0.71 and 0.54 events per patient-year, respectively). During a total treatment time of 104.1 patient-years 88 stone events occurred in 14 of 16 patients (0.84 events per patient-year).. D-penicillamine and alpha-mercaptopropionylglycine are effective in decreasing the rate of stone formation in patients in whom hydration and alkalization failed. While captopril may also be beneficial in this setting, it does not appear to be as effective as D-penicillamine or alpha-mercaptopropionylglycine, and it does not clearly add clinical benefit to those thiols. Our study demonstrates that patients with cystinuria are at high risk for recurrence when treated with any contemporary medical program. This natural history must be considered when evaluating the long-term efficacy of newer or alternative modes of medical and urological treatment.

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Captopril; Child; Child, Preschool; Cystinuria; Diuretics; Female; Follow-Up Studies; Humans; Infant; Male; Middle Aged; Penicillamine; Potassium Citrate; Sodium Bicarbonate; Tiopronin; Urinary Calculi

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.

Topics: Adolescent; Adult; Creatinine; Cystine; Cystinuria; Diet, Sodium-Restricted; Female; Humans; Kidney Tubules; Male; Sodium; Sodium Bicarbonate; Tiopronin

To evaluate medical treatments, in terms of adverse events (AEs) and therapeutic goals, in a large series of patients with cystinuria.. Data from 442 patients with cystinuria were recorded retrospectively. Crystalluria was studied in 89 patients. A mixed-effects logistic regression model was used to estimate how urine pH, specific gravity and cysteine-binding thiols (CBT) correlate with risk of cystine crystalluria.. Alkalizing agents and CBT agents were given to 88.8% (n = 381) and 55.3% (n = 238) of patients, respectively. Gastrointestinal AEs were reported in 12.3%, 10.4% and 2.6% of patients treated with potassium bicarbonate, potassium citrate and sodium bicarbonate, respectively (P = 0.008). The percentages of patients who experienced at least one AE with tiopronin (24.6%) and with D-penicillamine (29.5%) were similar (P = 0.45). Increasing urine pH and decreasing urine specific gravity significantly reduced the risk of cystine crystalluria, whereas D-penicillamine and tiopronin treatments did not reduce this risk (odds ratio [OR] 1 for pH ≤6.5; OR 0.52 [95% confidence interval {95% CI} 0.28-0.95] for 7.0 8.0, P <0.001).. Adverse events were frequent with D-penicillamine and tiopronin. Alkaline hyperdiuresis was well tolerated and reduced cystine crystalluria. Urine specific gravity ≤1.005 and urine pH >7.5, while warning about calcium-phosphate crystallization, should be the goals of medical therapy.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Cystinuria; Drug-Related Side Effects and Adverse Reactions; Female; France; Humans; Hydrogen-Ion Concentration; Infant; Male; Middle Aged; Penicillamine; Retrospective Studies; Sodium Bicarbonate; Tiopronin; Treatment Outcome; Urinalysis; Young Adult

Cystinuria is an inherited disorder characterized by defective renal reabsorption of cystine and dibasic amino acids leading to nephrolithiasis. This study was conducted to analyze the genotypes and phenotypes of pediatric patients with cystinuria. Eight children from Seoul National University Hospital and Asan Medical Center presenting with cystinuria from January 2003 to June 2016 were retrospectively analyzed. Mutational studies were performed by direct sequencing. Two of the 8 were male and 6 were female. The median ages at onset and diagnosis were 1.5 (range, 0.3-13.6) and 2.6 (range, 0.7-16.7) years, respectively. The median followed up was 7.7 (range, 3.4-14.0) years. Mutational analyses were performed in 7 patients and revealed biallelic SLC3A1 mutations (AA genotype) in 4 patients, a single heterozygous SLC3A1 mutation (A- genotype) in 1 patient, biallelic SLC7A9 mutations (BB genotype) in 1 patient, and a single heterozygous SLC7A9 mutation (B- genotype) in 1 patient. Two of the mutations were novel. No genotype-phenotype correlations were observed, except for earlier onset age in patients with non-AA genotypes than in patients with the AA genotype. All patients suffered from recurrent attacks of symptomatic nephrolithiasis, which lead to urologic interventions. At the last follow-up, 3 patients had a mild-to-moderate degree of renal dysfunction. This is the first study of genotypic and phenotypic analyses of patients with cystinuria in Korea.

Topics: Adolescent; Amino Acid Transport Systems, Basic; Amino Acid Transport Systems, Neutral; Asian People; Child; Child, Preschool; Cystinuria; DNA; DNA Mutational Analysis; Female; Genetic Association Studies; Genotype; Heterozygote; Humans; Infant; Male; Nephrolithiasis; Polymorphism, Genetic; Republic of Korea; Retrospective Studies; Sodium Bicarbonate; Tiopronin

We determined the immediate efficacy of contemporary urological intervention for cystine stones and the impact of such intervention on the subsequent rate of recurrent stone formation.. A total of 31 cystinuric patients underwent selected intervention for 61 stone events. Patients were subsequently followed at 6 to 12-month intervals while being treated with standard medical therapy. Logistic regression models were used to correlate potential risk factors with the efficacy of the intervention in achieving a stone-free status. Kaplan-Meier estimates of the probability of recurrence-free survivals at 1 and 5 years were generated, and risk factors for stone recurrence were analyzed using the log rank test.. Overall stone-free rate was 86.9%, which was not significantly influenced by the initial stone burden or type of intervention selected. The probability of recurrence-free survival at 1 and 5 years was 0.73 and 0.27, respectively, and again this probability was independent of initial stone burden or type of intervention selected. Urinary cystine levels before intervention and post-procedure residual stone status also failed to impact significantly on the risk of recurrence. However, a stone-free result, in contrast to residual stones, prolonged the mean time to stone recurrence from 346 to 1,208 days.. While cystine stones are not amenable to all currently available minimally invasive therapeutic modalities, high stone-free rates can be achieved without the need for open surgery and as such cystinuric patients clearly benefit from contemporary intervention. When such intervention is used selectively, with consideration given primarily to stone burden and location, rates of recurrence will relate primarily to the natural history of the medically treated cystinuric patient, and not the type of intervention applied.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alkalies; Cystine; Cystinuria; Disease-Free Survival; Female; Follow-Up Studies; Humans; Lithotripsy; Logistic Models; Male; Middle Aged; Minimally Invasive Surgical Procedures; Potassium Citrate; Probability; Recurrence; Risk Factors; Sodium Bicarbonate; Urinary Calculi

Cystinuria is an autosomal recessive disorder, and primary manifestation is the repeated formation of cystine calculi. Little information is available regarding clinical course of pediatric cystinuria having followed into adulthood. We report our experience with the management and the clinical course on cystinuria in children, who have been followed up for relatively long time.. We retrospectively reviewed the records of all pediatric patients with cystinuria in whom urolithiasis was treated from 1970 to 1996.. A total of 15 pediatric patients with cystine calculi (9 boys, 6 girls) were treated in our hospital. Average age at diagnosis was 3 years 4 months old. Mean follow-up was 104 months. Stone location was upper urinary tract in 11 cases, bladder in 3 cases and both upper urinary tract and bladder in 1 case. Medical treatments including hydration, urine alkalization and dissolution therapy were performed in all patients. In three cases whose urinary cystine level ranged from 138 to 326 mg/gCr, cystine calculi were disappeared by medical therapy alone. In one of 3 cases vesicoureteral reflux was identified. Side effects were noticed in 30.0% of patients with tiopronin and in 85.7% of those with D-penicillamine, especially in 1 case with tiopronin nephrotic syndrome being noticed. Surgical procedures were performed in 13 patients (lithotomy: 17 calculi, endourology: 7 calculi and ESWL: 7 calculi). The stone free rate was 100% with lithotomy, 80 to 100% with endourology and 43% with ESWL at an average of 5.9 procedures. No complications were recognized after the surgical treatments. The stone events of 15 patients ranged from 0 to 1.5 (average 0.55). In all six patients followed up over the age of 20 years, stone recurrences were observed exclusively between 17 and 20 years of age.. Dissolution therapy is more effective for cystinuric patients in whom urinary cystine excretion is less than 330 mg/gCr. For those cases with low urinary cystine level it is necessary to evaluate structural abnormalities of the urinary tract to avoid stone recurrence. ESWL and endourology should be tried for pediatric cystinuria except for neonates and infants, considering its safety. The patients and their parents must have adequate knowledge about the disease itself and its management. Prevention of cystine calculi recurrences depends on patient compliance to the therapeutic regimens necessitating close follow up according to the clinical conditions, especially for those in pubertic or postpubertic age.

Topics: Adolescent; Adult; Child; Child, Preschool; Cystinuria; Female; Follow-Up Studies; Humans; Infant; Lithotripsy; Male; Methionine; Penicillamine; Retrospective Studies; Secondary Prevention; Sodium Bicarbonate; Tiopronin; Urinary Calculi; Urologic Surgical Procedures

We determined the clinical efficacy of captopril for the prevention of new or stone growth in patients with homozygous cystinuria. Nine patients with a history of multiple cystine stones despite standard fluid and alkalization therapy received 50 mg. captopril, 3 times daily in addition to the standard therapy. Before treatment the rate of new stone formation or stone growth ranged from 0.7 to 2.0 events (mean 1.2) per patient-year for 1 to 3 years of observation (mean 1.9). During treatment the rate ranged from 0 to 3.0 events (mean 1.03) per patient-year for 0.5 to 6 years (mean 2.9). Although statistical significance was not evident for the group as a whole (p = 0.35), our findings suggest that captopril may be clinically efficacious in at least some patients with difficult to control cystinuria. Recommendations regarding its indications in this setting are made.

Topics: Adult; Aged; Captopril; Citrates; Citric Acid; Cystine; Cystinuria; Female; Fluid Therapy; Follow-Up Studies; Humans; Kidney Calculi; Male; Middle Aged; Sodium Bicarbonate; Treatment Outcome

Although cystine stones account for 1 to 3 per cent of renal calculi, many of these patients are difficult to manage because of recurrent urolithiasis. Seven cases of homozygous cystinuria are summarized. The evolution to the present treatment of percutaneous extraction and chemolysis appears to be the preferred form of treatment although extracorporeal shock wave lithotripsy (ESWL) may also be utilized. In addition, in vitro experiments were conducted to study the effectiveness of different chelating agents and buffers at different urinary pHs. The effect of cystinuric and noncystinuric urines was also evaluated.

Topics: Acetylcysteine; Adult; Ascorbic Acid; Bicarbonates; Cystine; Cystinuria; Female; Homozygote; Humans; Kidney Calculi; Male; Middle Aged; Penicillamine; Sodium; Sodium Bicarbonate; Tromethamine

Topics: Bicarbonates; Cystinuria; Humans; Kidney Calculi; Magnesium; Magnesium Compounds; Phosphates; Sodium Bicarbonate; Solubility; Struvite; Ultrasonic Therapy; Uric Acid; Urinary Bladder Calculi; Vibration

Topics: Adolescent; Adult; Aged; Bicarbonates; Child; Cystinuria; Female; Fluid Therapy; Follow-Up Studies; Homozygote; Humans; Male; Middle Aged; Penicillamine; Sodium Bicarbonate; Urinary Calculi