Cystine crystals in the urine
| HOSP # | MRN107595230 | WARD | Urology OPD |
| CONSULTANT | Prof George van der Watt | DOB/AGE | 16y female |
Abnormal Result
Urine amino acid screening by GCMS demonstrates massive elevations of cystine at 1842 nmol/mg creat (Ref<125), lysine at 10827 nmol/mg creat (Ref < 630) and ornithine at 2742 nmol/mg creat (Ref <91). Dibasic aminoaciduria at these levels is only seen in cystinuria. Our methodology does not detect arginine but in this scenario it would be similarly elevated.
Presenting Complaint
The patient, a 16 y female presented with signs and symptoms of an upper urinary tract infection.
History
No history of chronic medical illness, no medication. Generally have been well.
The patient did have a cousin, following up at Red Cross Children’s Hospital for congenital cystinuria.
Examination
Renal angle tenderness was noted. There were also symptoms of pain which radiated down to the inguinal area.
Laboratory Investigations
| March 2020 | The urine microscopy showed numerous (3+) leucocytes and numerous (3+) epithelial cells but no erythrocytes visible. Culture: <10 000 cfu/ml |
| April 2020 | Urinary cystine stones was observed in the urine upon microscopy with 3+ erythrocytes |
| April 2020 | 24h quantitative cystine: massive elevations of cystine at 1842 nmol/mg creat (<125), lysine at 10827 nmol/mg creat (< 630) and ornithine at 2742 nmol/mg creat (<91). Dibasic aminoaciduria at these levels is only seen in cystinuria. Creat MW = 113g/mol = 113 mg/mmol; Daily urine creatinine was 6 mmol/24h, thus 113 x 6 = 678 mg / 24h; hence dU cystine was 1842 nmol x 678 = 1 248 876 nmol / 24h = 1 248 umol/24h. Cystine MW = 121 g/mol = 121 ug/umol hence dU cystine was 121 x 1248 = 151 008 ug/24h = 151 mg/24h |
| October 2020 | A 5.2g brown jagged renal stone was removed, confirmed by Fourier Transform infrared spectroscopy to contain 50% calcium hydrogen phosphate and 50% cystine. |
| April 2021 | dU cystine requested again – results not out yet at time of writing. |
| April 2021 | Crystals in the urine reported to be constituted of uric acid – most likely a laboratory error |
Other Investigations
On roentgenological examination, cystine calculi are radiopaque (although not as much) like calcareous calculi, but are more rounded and homogeneous in appearance. They may attain a staghorn size.
Final Diagnosis
Cystinuria – to be genetically confirmed in a case series
Take Home Message
Cystinuria stones develop in patients with homozygous cystinuria. Homozygous cystinuria is characterized by urinary cystine excretion of more than 250 mg/g creatinine.
Aetiology
Cystine is sparingly soluble in urine and it rarely exceeds 1.7mM/liter. Its solubility is greater at higher pH and is enhanced by electrolytes and macromolecules. however, it rarely exceeds 1.7 mM/liter (400 mg/liter). Cystine stones may form when urinary cystine concentration exceeds the solubility of cystine.
Pathophysiology of Cystinuria
Normally, cystine is filtered and almost completely reabsorbed in the proximal nephron, so that less than 20 mg is excreted in urine each day. In cystinuria, the serum concentration and hence the renal filtered load of cystine are reduced. Exaggerated cystine excretion under this circumstance suggests a disturbance in renal handling of cystine. More than one defect can impair tubular reabsorption and back-diffusion of cystine.
Similar defects in transport of other dibasic amino acids are present. However, exaggerated renal excretion of these amino acids and cystine may not be due to a single transport defect. Increasing the filtered load of one of these amino acids does not necessarily augment the excretion of others.
The intestinal transport of dibasic amino acids may also be defective in cystinuria. The disorder has been classified into three types based on varying intestinal transport disturbances for these amino acids. The intestinal transport has been assessed by the in vitro uptake of radiolabeled amino acid by specimens of jejunal mucosa obtained by peroral biopsy and by studies of plasma cystine levels after oral cystine administration. In type I cystinuria, there is no uptake of cystine, lysine, or arginine by jejunal mucosa, and plasma cystine concentration is not elevated after an oral cystine load. Thus there is defective intestinal transport of all three dibasic amino acids. In types II and III, the intestinal transport of dibasic amino acids is disturbed but less severely than in the type I presentation. In type II, some cystine is taken up by jejunal mucosa but at a reduced rate, and oral cystine loading does not increase the plasma cystine level. In type III cystinuria, the uptake of cystine and lysine by jejunal mucosa is variably reduced and the increment in plasma cystine after oral cystine loading is blunted. In the homozygous state, all three types of cystinuria involve excessive renal excretion of all four dibasic amino acids. In the heterozygous state, type I cystinuria is characterized by normal cystine excretion, whereas types II and III have elevated cystine and lysine excretion (although not quite up to the level encountered in the homozygous state), probably because of a prevailing (although reduced) intestinal uptake of these amino acids. Recently, discrete mutations in the dibasic amino acid transporter gene have been found in certain cystinuric patients.
Diagnostic Criteria
The urinary sediment (preferably in fresh first morning void) should be examined for the presence of typical hexagonal cystine crystals. The urine sample should also be screened for “qualitative” cystine by the cyanidenitroprusside test. A positive reaction suggests that cystine excretion exceeds 75 mg/liter. A false-positive test may be encountered in patients with homocystinuria and acetonuria. On roentgenological examination, cystine calculi are radiopaque (although not as much) like calcareous calculi, but are more rounded and homogeneous in appearance. They may attain a staghorn size.
If these studies are suggestive of the presence of cystinuria, urinary cystine excretion should be quantitated. Urinary cystine exceeding 250 mg/g creatinine is usually diagnostic of homozygous cystinuria. Stones passed or removed should be analyzed. The presence of cystine provides a definitive diagnosis of cystinuria.
Treatment of Cystine Nephrolithiasis
A low-methionine diet has often been recommended for the control of cystine nephrolithiasis because methionine is a precursor of cystine. Although such a dietary maneuver may reduce cystine excretion, rigid methionine restriction is impractical. Dietary sodium restriction may also reduce cystine excretion, but this beneficial effect may be neutralized by reduced solubility of cystine resulting from loss of the “solubilizing” action of sodium.
In patients with cystine calculi and moderate cystinuria [1 to 2 mM/day (250 to 500 mg/day)], conservative measures of high fluid intake and alkali administration should be attempted. The aim of fluid therapy is to increase urine volume sufficiently to reduce the cystine concentration below the solubility limit. At least 3 liters of fluid should be provided, including two 8-oz glassfuls with each meal and at bedtime. Patients should be directed to wake up at night to urinate and drink water. Additional fluids should be consumed when excessive sweating or intestinal fluid loss is present. A minimum urine output of 2 liters/day on a consistent basis is attainable by most patients with proper and persistent instruction.
In theory, alkali therapy would enhance cystine solubility by raising urinary pH. However, substantial increases in cystine solubility do not occur until the urinary pH exceeds 7.5. The provision of alkali, no matter how much, rarely raises urinary pH above 7.5. When urinary pH increases above 7.0 with alkali therapy, calcium phosphate nephrolithiasis may be enhanced because of the enhanced urinary supersaturation of hy- droxyapatite in an alkaline environment. Excessive alkali therapy therefore is not indicated.
Thus a modest amount of alkali is recommended to maintain urinary pH in a high normal range (6.5 to 7.0). Potassium citrate has the advantages over sodium citrate that it does not cause hypercalciuria, is less likely to promote development of calcium stones, and does not induce increased cystine excretion.
The object of treatment with penicillamine or tiopronin (α-mercaptopropionylglycine) is to reduce total cystine excretion by complexing cysteine, the monomeric form of cystine. Penicillamine or tiopronin may be added to the conservative treatment program in patients with moderate cystinuria when the conservative treatment is ineffective in controlling stone formation. In patients with severe cystinuria [> 2 mM/day (> 500 mg/day)], in whom conservative management alone is not likely to be effective, penicillamine or tiopronin therapy (together with conservative measures) may be begun.
Penicillamine and tiopronin share with cysteine a free sulfhydryl group. Thus, they undergo thiol-disulfide exchange with cystine to form penicillamine-cysteine or tiopronicysteine disulfide, which is much more soluble than cystine. After oral administration, a sufficient amount of penicillamine or tiopronin can be excreted in urine to complex cysteine and thereby lower cystine excretion. Unfortunately, penicillamine therapy is associated with frequent and sometimes severe side effects,including nephrotic syndrome, dermatitis, and pancytopenia. Tiopronin has biochemical and clinical actions similar to those of penicillamine. However, it has a lower toxicity profile than penicillamine.