Medical Info: Cystinuria
Cystinuria is an autosomal recessive defect in reabsorptive transport of cystine and the dibasic amino acids ornithine, arginine, and lysine from the luminal fluid of the renal proximal tubule and small intestine. The only phenotypic manifestation of cystinuria is cystine urolithiasis, which often recurs throughout a patient's lifetime. Surgical intervention is necessary, but the cornerstones of treatment are dietary and medical prevention of recurrent stone formation.
In 1810, Wollaston first described a different type of urinary calculi from the urinary bladder and coined the term "cystic oxide." Berzelius recognized that the compound was not an oxide, and he named it "cystine" because the material originated from the bladder. In 1908, Sir Archibald Garrod identified cystinuria as one of the original "inborn errors of metabolism." Yeh et al and Dent and Rose showed abnormal excretion of the dibasic amino acids lysine, arginine, and ornithine in persons with cystinuria. In 1955, Harris et al reported the complex autosomal recessive pattern of inheritance of cystinuria. In 1961, Milne et al demonstrated reduced intestinal absorption of dibasic amino acids in persons with cystinuria.
In 1954, while studying skin sensitivity to penicillin and its derivatives, Tabachnick et al noted that one of the degradation products of penicillin, penicillamine, reacted with cystine to form a mixed disulfide: penicillamine cysteine. In 1963, Crawhall et al first used penicillamine to manage cystinuric patients.
In recent years, understanding of the genetic and molecular components of cystinuria has advanced. In 1993, Lee et al cloned a human cDNA (rBAT [renal basic amino acid transporter]) in chromosome 2 encoding a transport protein for cystine and dibasic amino acids. In 1997, Bisceglia et al identified type III cystinuria on band 19q13.1.
Medical info:
Treatment:
Management algorithm
Overall, for a cystinuric patient without a stone, first-line therapy in the majority of cases is a conservative approach, including large-volume fluid intake (urine output >2.5 L/d), regular urine pH monitoring (urine pH of 7.5 and <8.0), dietary restrictions, and urinary alkalization with potassium citrate.
If this standard therapy fails to achieve the urinary cystine concentration of 300 mg/L, then medical therapy with D-penicillamine, alpha-MPG, or captopril must be added.
Treat patients with stone disease according to the location of the stone. The expertise of a urologist and a radiologist is important for decision-making processes, and stone site and size also influence further management (see Image 7).
Hydration
The average homozygous cystinuric patient excretes 600-1400 mg of cystine per day. The solubility of cystine at a pH of 7.0 is 250-300 mg/L. Therefore, one of the oldest and most effective cystine stone–prevention techniques is hyperdiuresis to decrease urinary cystine concentration. Early studies by Dent et al in the 1960s showed that hydration alone could prevent stone recurrence in up to a third of patients. This finding has been corroborated by more recent studies.
The goals of hydration therapy are urine volumes in excess of 3 L/d. This goal may require ingesting 4-4.5 L of water per day. Patients should drink 240 mL of water every hour during the day and 480 mL before retiring and at least once during the night.
Alkalizing beverages, such as mineral water, rich in bicarbonate and low in sodium (1500 mg HCO3/L, maximum 500 mg sodium/L), and citrus juices are preferred.
Patients should monitor the specific gravity of their urine using Nitrazine dipsticks, with a goal of achieving a value less than 1.010.
Alkalinization
Alkaline urine can prevent the precipitation of cystine calculi and can even aid in dissolution. Urine pH must be more than 7.5 for stone dissolution to occur.
Paradoxically, urine pH of more than 7.5 can cause a predisposition to the formation of calcium phosphate calculi, so urine must be monitored with dipsticks to maintain a pH of 7.0-7.5 for stone prevention.
Currently, Nitrazine paper and standard pH dipsticks have no clear color differentiations in the range of 6.0-7.5 pH. UriDynamics, a small company in Indianapolis, Ind, has developed a new test strip called StoneGuard II. This strip includes an additional color block at a pH of 7.5. The colors produced are yellow-orange (pH 5.0), yellow-green (pH 6.0), green-yellow (pH 6.5), light green (pH 7.0), green with blue cast (pH 7.5), and greenish blue (pH 8.0). No interference from common medications, nutritional supplements, or blood has been observed. It also has a pad to measure specific gravity over a range of 1.000-1.030.
Sodium bicarbonate was used in the past but is no longer recommended as a first-line agent. The sodium ion may actually increase the amount of cystine excreted.
Potassium citrate is the first-line alkalinizing drug. The typical adult dose is 60-80 mEq/d divided into 3-4 doses (15-20 mL/d), titrating the dose as needed to maintain a urine pH within the target range of 7.0-7.5.
Acetazolamide inhibits the brush-border carbonic anhydrase of the proximal convoluted tubule, thereby increasing urinary bicarbonate excretion. Acetazolamide is not widely used as a first-line drug and is of questionable efficacy.
With any alkalinization therapy, monitoring of urinary pH is essential.
In 1810, Wollaston first described a different type of urinary calculi from the urinary bladder and coined the term "cystic oxide." Berzelius recognized that the compound was not an oxide, and he named it "cystine" because the material originated from the bladder. In 1908, Sir Archibald Garrod identified cystinuria as one of the original "inborn errors of metabolism." Yeh et al and Dent and Rose showed abnormal excretion of the dibasic amino acids lysine, arginine, and ornithine in persons with cystinuria. In 1955, Harris et al reported the complex autosomal recessive pattern of inheritance of cystinuria. In 1961, Milne et al demonstrated reduced intestinal absorption of dibasic amino acids in persons with cystinuria.
In 1954, while studying skin sensitivity to penicillin and its derivatives, Tabachnick et al noted that one of the degradation products of penicillin, penicillamine, reacted with cystine to form a mixed disulfide: penicillamine cysteine. In 1963, Crawhall et al first used penicillamine to manage cystinuric patients.
In recent years, understanding of the genetic and molecular components of cystinuria has advanced. In 1993, Lee et al cloned a human cDNA (rBAT [renal basic amino acid transporter]) in chromosome 2 encoding a transport protein for cystine and dibasic amino acids. In 1997, Bisceglia et al identified type III cystinuria on band 19q13.1.
Medical info:
Treatment:
Management algorithm
Overall, for a cystinuric patient without a stone, first-line therapy in the majority of cases is a conservative approach, including large-volume fluid intake (urine output >2.5 L/d), regular urine pH monitoring (urine pH of 7.5 and <8.0), dietary restrictions, and urinary alkalization with potassium citrate.
If this standard therapy fails to achieve the urinary cystine concentration of 300 mg/L, then medical therapy with D-penicillamine, alpha-MPG, or captopril must be added.
Treat patients with stone disease according to the location of the stone. The expertise of a urologist and a radiologist is important for decision-making processes, and stone site and size also influence further management (see Image 7).
Hydration
The average homozygous cystinuric patient excretes 600-1400 mg of cystine per day. The solubility of cystine at a pH of 7.0 is 250-300 mg/L. Therefore, one of the oldest and most effective cystine stone–prevention techniques is hyperdiuresis to decrease urinary cystine concentration. Early studies by Dent et al in the 1960s showed that hydration alone could prevent stone recurrence in up to a third of patients. This finding has been corroborated by more recent studies.
The goals of hydration therapy are urine volumes in excess of 3 L/d. This goal may require ingesting 4-4.5 L of water per day. Patients should drink 240 mL of water every hour during the day and 480 mL before retiring and at least once during the night.
Alkalizing beverages, such as mineral water, rich in bicarbonate and low in sodium (1500 mg HCO3/L, maximum 500 mg sodium/L), and citrus juices are preferred.
Patients should monitor the specific gravity of their urine using Nitrazine dipsticks, with a goal of achieving a value less than 1.010.
Alkalinization
Alkaline urine can prevent the precipitation of cystine calculi and can even aid in dissolution. Urine pH must be more than 7.5 for stone dissolution to occur.
Paradoxically, urine pH of more than 7.5 can cause a predisposition to the formation of calcium phosphate calculi, so urine must be monitored with dipsticks to maintain a pH of 7.0-7.5 for stone prevention.
Currently, Nitrazine paper and standard pH dipsticks have no clear color differentiations in the range of 6.0-7.5 pH. UriDynamics, a small company in Indianapolis, Ind, has developed a new test strip called StoneGuard II. This strip includes an additional color block at a pH of 7.5. The colors produced are yellow-orange (pH 5.0), yellow-green (pH 6.0), green-yellow (pH 6.5), light green (pH 7.0), green with blue cast (pH 7.5), and greenish blue (pH 8.0). No interference from common medications, nutritional supplements, or blood has been observed. It also has a pad to measure specific gravity over a range of 1.000-1.030.
Sodium bicarbonate was used in the past but is no longer recommended as a first-line agent. The sodium ion may actually increase the amount of cystine excreted.
Potassium citrate is the first-line alkalinizing drug. The typical adult dose is 60-80 mEq/d divided into 3-4 doses (15-20 mL/d), titrating the dose as needed to maintain a urine pH within the target range of 7.0-7.5.
Acetazolamide inhibits the brush-border carbonic anhydrase of the proximal convoluted tubule, thereby increasing urinary bicarbonate excretion. Acetazolamide is not widely used as a first-line drug and is of questionable efficacy.
With any alkalinization therapy, monitoring of urinary pH is essential.
posted by Jul at
1:59 PM
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