Case Studies

Received 3.27.06 | Revisions Received 5.22.06 | Accepted 5.23.06

Recurrent Nephrolithiasis in a 9-Year-Old Child

Monte S. Willis, MD, PhD
(University of North Carolina, Chapel Hill, NC)
DOI: 10.1309/FJWXLGEXWG820WLB

Clinical History Past Medical History Principal Laboratory Findings

Patient Non-contributory. Table 1
9 ½ year-old female.
Family History Additional Diagnostic Procedures
Chief Complaint Non-contributory. Renal ultrasonography demonstrated kidneys

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Recurrent kidney stones.
History of Present Illness
The child’s parents reported she had
experienced 2 previous episodes of kidney
stones (nephrolithiasis) within the last 10
months. These episodes were associated with
fever, intense abdominal pain, back pain, and
vomiting. Kidney stones were identified by CT
scan as the cause of these symptoms.
Physical Exam
Vital signs: blood pressure, 107/70 mmHg;
temperature, 37.4°C; pulse, 112 bpm. Height:
134 cm (approximately 50th percentile for
age/gender); weight, 28.7 kg (approximately
50th percentile for age/gender); body mass
index (BMI), 15.8.
that were normal in size and echotexture with
no evidence of hydronephrosis or masses.
However, 2 areas of echogenic foci
representing renal calculi were identified in the
right kidney (Image 1). No distinct renal calculi
were identified in the left kidney.

Questions
Table 1_Principal Laboratory Findings
1. What are this patient’s most striking clinical and laboratory
Test Patient’s Result Reference Interval
findings?
2. How do you explain these findings? Chemistry
3. What is the differential diagnosis and how can this patient’s Creatinine, serum 0.6 0.4-0.9 mg/dL
clinical and laboratory findings be used to differentiate Creainine, urine (24 h) 486 800-2,800 mg/dL
between these diagnoses? Urinalysis
4. What is this patient’s most likely diagnosis? Macroscopic: Leuckocyte esterase 1+ Negative
Blood/hemoglobin 1+ Negative
5. Under what conditions should this patient’s diagnosis be Microscopic: RBCs/hpf 3-5 Negative
suspected? Crystals Clear, hexagonal Negative
6. What is the epidemiology and basic defect in this patient’s plates
disease? Special Chemistry
Urine amino acid analysis: (Ages 3-15 years)
7. What is the molecular pathogenesis of this patient’s disease? Cystine 796 11-53 µmol/24 h
8. What is the medical therapy used in the treatment of this Lysine 3,665 19-140 µmol/24 h
patient’s condition? Ornithine 966 3-16 µmol/24 h
9. What other treatment modalities have been used in the Arginine 2,116 10-25 µmol/24 h
treatment of this patient’s condition? RBCs, red blood cells; hpf, high power field.

Possible Answers secondary to calculous formation.1 Under high power microscopy,

1. The most striking clinical finding is a history of recurrent
kidney stones in a child. Significant laboratory findings include:
a normal urine (random and 24 hour) creatinine concentration;
a urinalysis positive for leukocyte esterase, hemoglobin, and red
blood cells (RBCs); the presence of clear hexagonal crystals on
urine microscopic analysis (Image 2); and abnormally elevated
urinary concentrations of cystine, ornithine, lysine, and arginine
(Table 1).
2. Leukocyte esterase activity in a urine specimen indicates
the presence of neutrophil esterolytic activity. Therefore, a posi-
tive urine leukocyte esterase test indicates the presence of a sig-
nificant number of intact or lysed neutrophils associated
typically with a urinary tract infection. In a patient with recur-
rent kidney stones, this may be due to stasis-associated ascend-
ing infection or to a localized mucosal inflammatory response
unstained RBCs in the urine are normally found in small
numbers [0-2 cells/high power field (hpf )]. More than 3
cells/hpf, as found in this case, is considered abnormal and can
be the result of calculi formation.1 Urine amino acid testing is
often performed to screen for congenital abnormalities of
amino acid metabolism.
3. Four disease entities that exhibit abnormal transport of
the cationic amino acids (ie, cystine, ornithine, lysine, and argi-
nine) found in our patient’s urine include: (1) classic cystinuria,
(2) lysinuric protein intolerance (LPI), (3) hyperdibasic
aminoaciduria type 1, and (4) isolated lysinuria (lysine malab-
sorption syndrome).2,3 The symptoms of LPI and hyperdibasic
aminoaciduria type 1 include vomiting and diarrhea after wean-
ing.4,5 The hyperammonemia associated with protein ingestion
leads to avoidance of high protein foods after which a host of

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Case Studies
Image 1_Ultrasound of the right kidney illustrating at least 2
echogenic foci with posterior acoustic shadowing which were consis-
tent with renal calculi (arrows).
medical problems ensue including poor growth, enlarged liver
and spleen, osteoporosis, muscle hypotonia, and mental retarda-
tion.5 The single patient with isolated lysinuria identified to date
suffered from growth failure, seizures, and mental retardation.
Therefore, our patient’s clinical (normal mental status and
growth) and laboratory findings rule out LPI, hyperdibasic
aminoaciduria type 1, and isolated lysinuria as the cause of her
recurrent nephrolithiasis, leaving cystinuria as the most likely
cause of our patient’s disease.
4. Most likely diagnosis: cystinuria. The patient’s history of
recurrent nephrolithiasis, the presence of hexagonal crystals in
the urine, and significantly elevated concentrations of cystine,
ornithine, lysine, and arginine in a 24-hour urine specimen
support the diagnosis of cystinuria.
5. The diagnosis of cystinuria should be suspected in pa-
tients with cystine stones, especially if they have a family history
of cystine nephrolithiasis. Up to 10% of urinary stones that
occur in children are caused by cystinuria.6 More than 50% of
patients with cystinuria develop cystine stones in their lifetime,
most of which form stones recurrently and require the need for
repeated interventions.7 Cystine stones can be detected by ultra-
sound and are difficult to visualize by x-ray imaging. Hexagonal
crystals detected by urinalysis can confirm the diagnosis; how-
ever, only 20% to 25% of patients with cystinuria have
detectable crystals.8 Due to this fact, definitive diagnosis of
cystinuria is made by quantifying urine amino acids in a 24-
hour urine specimen using ion-exchange chromatography, high
performance liquid chromatography (HPLC), or tandem mass
spectrometry (MS/MS).9-11 Simpler methods utilizing colori-
metric assays have been described as an economical method for
population screening for this disease.12,13
6. Cystinuria is an autosomal recessive disease with a preva-
lence estimated between 1:1,000 to 1:17,000 in the United
States and Europe.14,15 The basic defect in cystinuria is impaired
transport of dibasic amino acids in the proximal renal tubule.
While this defect results in elevated urine concentrations of cys-
tine, ornithine, lysine, and arginine, only cystine is insoluble
enough in urine to form stones, particularly at pH 5-7. A 3-fold
increase in solubility occurs when the pH is >8, which is why
this disease has been treated by urine alkalinization for nearly 5
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Image 2_Example of the clear, hexagonal crystals found in our
patient’s urine.
decades.16 In addition, to more accurately quantify urine cystine
concentration, the solubility of cystine can be enhanced by
adding sodium bicarbonate to urine samples until the pH is
greater than 7.5.17 While a 24-hour urine collection is optimal
to determine cystine levels, the cystine/creatinine ratio on a ran-
dom urine sample may distinguish individuals with homozygous
disease from heterozygous carriers. A random urine cystine/crea-
tine ratio can also be used to monitor therapy. It should be
noted, however, that the urinary excretion level of cystine (and
other dibasic amino acids such as ornithine, lysine, arginine)
does not correlate with the frequency of cystine stone formation.
Therefore, whenever possible, it is important to analyze kidney
stone content, as renal stones composed of complex mixtures of
amino acids and other substances can occur, requiring further, or
different, interventions than might occur in the presence of pure
cystine stones.
7. There is growing evidence that kidney stone formation is
associated with specific mutations in calcium, oxalate, uric acid,
and cystine transporters in the kidney.18 The molecular basis of
cystinuria involves 2 mutations in the renal dibasic amino acid
transporter.19,20 The mutation in the SLC3A1 gene, found on
chromosome 2, encodes the rBAT subunit of this transporter
(Figure 1). The second mutation in the SLC7A9 gene, found
on chromosome 19, encodes the b0+AT region of the
transporter.Cystinuria has recently been re-classified following
the identification of these molecular defects into three types:
Type A (SLC3A1 mutation only); Type B (SLC7A9 mutation
only); or Type AB (having both SLC3A/SLC7A9 mutations).21
Abnormalities in one or both of these genes identifies 75% of all
affected individuals with cystinuria, suggesting that there remain
unidentified mutations in the renal di-basic amino acid trans-
porter.18 While progress has been made in identifying the muta-
tions associated with cystinuria, it is not necessary clinically to
detect these specific underlying mutations by molecular meth-
ods, as they can be accurately predicted based on the results of
standard laboratory test values.18 Patients with homozygous mu-
tations in genes associated with cationic amino acid transport
proteins have urine cystine concentrations exceeding 1,300
µmol/L.8,22 Alternatively, healthy individuals excrete less than
100 µmol/L. Patients with heterozygous mutations may have
urine cystine concentrations <100 µmol/L; however, they can be
distributed in the normal range and extend up to, but typically
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do not exceed, 1,000 µmol/L.8,22 Recurrent kidney stones
(nephrolithiasis) result from a diversity of mechanisms, many
of which involve mutations in various transport proteins. In
contrast to individuals that do not form calcium renal stones,
patients that form stones made primarily of calcium have been
shown to have specific mutations in genes (eg, CLCN5 and
CLCNKB, WNK Kinases, ATPB61, and NPT2) that regulate
renal chloride excretion and reabsorption.18 Similarly, hyperox-
aluria has been associated with mutations in the AGXT and
GRHPR genes and defects in the glyoxalate metabolic
pathway.18 Moreover, distinct mutations in the cystine transport
protein genes SLC3A1 and SLC7A9 have been shown to lead to
cystine stones associated with cystinuria. In addition, hyperuri-
cosuria, the underlying cause of uric acid stones, has been associ-
ated with familial clusters of gene mutations in uric acid
transport proteins. Taken together, these findings explain the
growing appreciation of the role of specific gene mutations in
the pathogenesis of nephrolithiasis.18
8. Medical therapy in the treatment of cystinuria involves
regular examinations, dietary methionine restriction, and phar-
macological therapy. Since the metabolism of methionine results
in cystine, dietary restriction of methionine, found in protein-
rich foods, would be ideal. However, such strict restriction is not
followed by most patients and not recommended in children,
as in the present case. However, a low protein diet (<0.8 g pro-
tein/day) is recommended in concert with a reduction in salt
intake, which has been shown to reduce cystine excretion.23
Fluid intake of at least 4-5 L of water per day (3 L in children)
will dilute urinary cystine concentrations and reduce precipita-
tion. Intake should ensure diuresis throughout the night, in-
cluding the post-micturation period.24,25 Alkalinization of the
urine increases the solubility of cystine, so administration of
potassium citrate is recommended in patients with severe renal
disease. To adequately alkalinize the urine, urinary pH determi-
nation should initially be made at least 3 times a day. High alka-
linization of the urine carries the risk of calcium phosphate
kidney stone formation. If these methods fail, agents that induce
the conversion of cystine to cysteine can be used if cystine excre-
tion is >3 mmol/day.8 The most widely used agents for this
purpose are D-penicillamine and α-mercaptopropionylglycine
Figure 1_The heterodimeric amino acid transporter protein, consist-
ing of b0+AT and rBAT regions, transports cystine in the proximal
renal tubule. Mutations in the SLC3A1 (rBAT) gene are detected in
most cases of Type A cystinuria. Adapted from Verrey, et al.33
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Case Studies
(MPG), which effectively cleave the disulfide bond of cystine
to form cysteine (Figure 2), resulting in a 50-fold increase in
solubility.26-28 High dose ascorbic acid acts similarly by cleaving
the disulfide bond in cystine. Unfortunately, the treatment of
patients with cystinuria by these various modalities has limited
efficacy, major side effects, and high recurrence rates resulting in
poor patient compliance and a high risk of renal impairment
over time.
9. In addition to medical therapy to prevent kidney stones,
shock wave lithotripsy, uteroscopy and laser lithotripsy, percuta-
neous nephrolithotome, open surgery, and renal transplantation
can be utilized to remove kidney stones once they are formed.
Shock wave lithotripsy is a non-invasive method to disrupt
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upper urinary tract stones <1.5 cm in size. Uteroscopy and laser
lithotripsy can be used on larger stones (1.5 to 2 cm), while per-
cutaneous nephrolithotomy may be utilized when stones are >2
cm in diameter. For larger, complex stones, open surgery may be
necessary. Renal transplantation has been performed on patients
with renal failure precipitated by cystine renal stones. Interest-
ingly, it appears that recurrent nephrolithiasis does not occur in
transplanted kidneys as would be expected based on the patho-
physiology of this disease.29-32
Patient follow-up: The patient’s parents were instructed to
increase the patient’s fluid intake to 3 L/day, alkalinize the urine
with Polycitra-K (potassium citrate, 7.5 mL b.i.d.), and monitor
the child’s urine pH. Two months later, no intervening abdomi-
nal, pelvic, or flank pain, or gross hematuria, was reported. Daily
urine pH values were consistently in excess of 7, and the child
had been compliant with her increased fluid intake. No crystals
were found in her urine, and a renal ultrasound revealed only
persistent small stones in the right kidney. LM
Keywords: cystinuria, cystine, nephrolithiasis, kidney stones, crys-
tals, inborn errors of metabolism, rBAT, b0+AT
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to cysteine, a form 50-fold more water soluble than cystine.
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