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Volume 145, Issue 5
May 2020

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Case Reports| May 01 2020


Α-LIPOIC ACID (ALA) IMPROVES CYSTINE SOLUBILITY IN CYSTINURIA: REPORT OF 2 CASES

Onur Cil, MD, PhD;
Onur Cil, MD, PhD
Division of Pediatric Nephrology, Department of Pediatrics, University of
California, San Francisco, San Francisco, California
Address correspondence to Onur Cil, MD, PhD, Division of Pediatric Nephrology,
Department of Pediatrics, University of California, San Francisco, 550 16th St,
San Francisco, CA 94158. E-mail: onur.cil@ucsf.edu
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Farzana Perwad, MD
Farzana Perwad, MD
Division of Pediatric Nephrology, Department of Pediatrics, University of
California, San Francisco, San Francisco, California
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Address correspondence to Onur Cil, MD, PhD, Division of Pediatric Nephrology,
Department of Pediatrics, University of California, San Francisco, 550 16th St,
San Francisco, CA 94158. E-mail: onur.cil@ucsf.edu

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no
potential conflicts of interest to disclose. Patients and parents were provided
detailed information about the potential side effects of cystine-binding drugs
versus α-lipoic acid, and after detailed discussions, they decided to use the
nutritional supplement α-lipoic acid. Patients and parents provided consent for
publication of medical information.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial
relationships relevant to this article to disclose

Pediatrics (2020) 145 (5): e20192951.
https://doi.org/10.1542/peds.2019-2951
Article history
Accepted:
November 07 2019

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Citation

Onur Cil, Farzana Perwad; α-Lipoic Acid (ALA) Improves Cystine Solubility in
Cystinuria: Report of 2 Cases. Pediatrics May 2020; 145 (5): e20192951.
10.1542/peds.2019-2951

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Cystinuria is an autosomal recessive disorder characterized by excessive urinary
excretion of cystine, resulting in recurrent cystine kidney stones, often
presenting in childhood. Current treatment options for cystinuria include
dietary and/or fluid measures and potassium citrate to reduce cystine excretion
and/or increase solubility. Tiopronin and D-penicillamine are used in refractory
cases to bind cystine in urine, albeit with serious side effects. A recent study
revealed efficacy of nutritional supplement α-lipoic acid (ALA) treatment in
preventing kidney stones in a mouse model of cystinuria. Here, we report 2
pediatric patients (6 and 15 years old) with cystinuria who received regular
doses of ALA in addition to conventional therapy with potassium citrate. Both
patients tolerated ALA without any adverse effects and had reduced frequency of
symptomatic and asymptomatic kidney stones with disappearance of existing kidney
stones in 1 patient after 2 months of ALA therapy. ALA treatment markedly
improved laboratory markers of cystine solubility in urine with increased
cystine capacity (−223 to −1 mg/L in patient 1 and +140 to +272 mg/L in patient
2) and decreased cystine supersaturation (1.7 to 0.88 in patient 1 and 0.64 to
0.48 in patient 2) without any changes in cystine excretion or urine pH. Our
findings suggest that ALA improves solubility of cystine in urine and prevents
stone formation in patients with cystinuria who do not respond to diet and
citrate therapy.

Subjects:
Nephrology
Topics:
cystine, cystinuria, solubility, nephrolithiasis, potassium citrate, urine,
calculi, urine ph, citrates, kidney calculi

Cystinuria is an autosomal recessive disorder characterized by increased urinary
cystine excretion and recurrent nephrolithiasis.1  Cystine stones often
necessitate multiple procedures and/or surgeries for removal,2  and patients
with cystinuria have higher incidence of chronic kidney disease compared to
other stone formers.3,4  Urinary cystine excretion is normally <30 mg per day
and is greatly increased (generally >400 mg per day) in cystinuria. To keep
urine cystine concentration below the solubility limit (∼250 mg/L at pH 7),5 
patients with cystinuria often must have high urine output, which requires high
fluid intake and can be challenging in children. Potassium citrate is frequently
prescribed to alkalinize urine and increase cystine solubility. Reducing sodium
and protein intake is also recommended to decrease cystine excretion.
Conservative measures (fluid and/or diet changes, citrate) frequently fail,5 
and patients often require cystine-binding drugs (D-penicillamine and
tiopronin), which act by interfering with cysteine dimerization.6  These drugs
have variable efficacy and can cause serious side effects such as nephrotic
syndrome, hepatotoxicity, and pancytopenia.7  There is a large unmet need for
safer and more efficacious treatments for cystinuria.

α-lipoic acid (ALA) is a dietary supplement commonly used in diabetic neuropathy
for its antioxidant effects.8  In a recent study, authors reported efficacy of
ALA (dose equivalent to ∼40 mg/kg per day in humans) in preventing stone
formation in a mouse model of cystinuria.9  Here, we report use of ALA
supplementation in 2 pediatric patients with cystinuria and demonstrate its
efficacy in improving key urine markers of cystine solubility (cystine
supersaturation and capacity).

Urine tests for cystine solubility were performed by Litholink Corporation
(Chicago, IL) as part of routine clinical care. Patients used 300- or 600-mg ALA
capsules manufactured by Natrol LLC (Los Angeles, CA).


CASE REPORT




PATIENT 1

A 6-year-old girl with a history of recurrent intermittent abdominal pain since
3 years of age was diagnosed with nephrolithiasis by renal ultrasound that
revealed a 4-mm left ureterovesical junction stone with moderate
hydroureteronephrosis. She subsequently passed a 4-mm stone that was confirmed
to be composed of cystine by stone analysis and was referred to the
comprehensive pediatric kidney stone center at the University of California, San
Francisco. Her initial 24-hour urine collection revealed low urine volume (0.75
L), high cystine excretion (408 mg per day), high cystine supersaturation (1.7)
and low cystine capacity (−223 mg/L) with a pH of 7.44 (goal >7.0), and normal
urinary calcium and citrate excretions (Table 1). She was diagnosed with
cystinuria and recommended to increase fluid and limit sodium intake. Her
follow-up 24-hour urine collection after 5 months revealed hypercalciuria (7.9
mg/kg per day) with a lower urine pH (7.2), and she was started on potassium
citrate (0.5 mEq/kg BID [twice daily]). Despite increased urine volume (1.1–1.3
L) and slightly higher urine pH (7.4) with citrate therapy, her cystine
supersaturation and capacity remained unchanged in subsequent urine analyses.
She continued to have intermittent abdominal pain with no stones detected on
repeat ultrasound. She was started on ALA supplementation (300 mg daily; 17
mg/kg per day or ∼400 mg/m2 per day) and continued using potassium citrate.
After 1 month of ALA treatment, there were substantial improvements in urine
cystine capacity (from −222 to −62 mg/L) and cystine supersaturation (from 1.7
to 1.0). Her ALA dose was increased to 300 mg BID (34 mg/kg per day or ∼800
mg/m2 per day), and she started drinking more water motivated by the improvement
in urine tests. Her most recent 24-hour urine analysis revealed further
improvements in cystine supersaturation (0.88) and capacity (−1 mg/L). She
reported no adverse events with this therapy. During the 11-month follow-up
after starting ALA, her episodes of abdominal pain completely resolved and her
surveillance ultrasounds have not revealed any stones.

TABLE 1

Twenty-four–Hour Urine Parameters of Patient 1 and 2 Before and After ALA
Therapy

Treatment . Urine Volume, L/d . Urine pH . Cystine Excretion, mg/d . Cystine
Supersaturation . Cystine Capacity, mg/L . Creatinine Excretion, mg/kg per d
. Calcium Excretion, mg/kg per d . Citrate Excretion, mg/g Creatinine . PCR,
g/kg per d . Sodium Excretion, mmol/d . Patient
1            Baseline 0.75 7.44 408 1.7 −223 21.6 3.4 1036 1.8 78  Baseline 1.28 7.20 632 1.63 −226 23.1 7.9 1135 2.6 71  Potassium
citrate 1.08 7.39 630 1.7 −222 21.8 4.6 1218 2.1 79  Potassium citrate +
lower-dose ALA 1.42 7.53 464 1.09 −62 18.9 5.4 1251 1.6 45  Potassium citrate +
higher-dose ALA 2.13 7.31 587 0.88 −1 19.2 8.1 1324 2.3 99 Patient
2            Low-dose Potassium
citrate 1.5 7.57 n/a n/a n/a 27.6 1.3 307 n/a 146  High-dose Potassium
citrate 4.55 8.0 623 0.35 294 27.5 1.1 805 1.0 145  Moderate-dose Potassium
citrate 4.5 7.76 662 0.47 145 21.3 0.6 592 0.9 105  Moderate-dose Potassium
citrate 2.87 7.80 700 0.64 140 21.5 1.0 664 0.9 122  Moderate-dose Potassium
citrate + ALA 1.96 7.98 545 0.48 272 18.9 0.7 664 0.7 62 

Treatment . Urine Volume, L/d . Urine pH . Cystine Excretion, mg/d . Cystine
Supersaturation . Cystine Capacity, mg/L . Creatinine Excretion, mg/kg per d
. Calcium Excretion, mg/kg per d . Citrate Excretion, mg/g Creatinine . PCR,
g/kg per d . Sodium Excretion, mmol/d . Patient
1            Baseline 0.75 7.44 408 1.7 −223 21.6 3.4 1036 1.8 78  Baseline 1.28 7.20 632 1.63 −226 23.1 7.9 1135 2.6 71  Potassium
citrate 1.08 7.39 630 1.7 −222 21.8 4.6 1218 2.1 79  Potassium citrate +
lower-dose ALA 1.42 7.53 464 1.09 −62 18.9 5.4 1251 1.6 45  Potassium citrate +
higher-dose ALA 2.13 7.31 587 0.88 −1 19.2 8.1 1324 2.3 99 Patient
2            Low-dose Potassium
citrate 1.5 7.57 n/a n/a n/a 27.6 1.3 307 n/a 146  High-dose Potassium
citrate 4.55 8.0 623 0.35 294 27.5 1.1 805 1.0 145  Moderate-dose Potassium
citrate 4.5 7.76 662 0.47 145 21.3 0.6 592 0.9 105  Moderate-dose Potassium
citrate 2.87 7.80 700 0.64 140 21.5 1.0 664 0.9 122  Moderate-dose Potassium
citrate + ALA 1.96 7.98 545 0.48 272 18.9 0.7 664 0.7 62 

Treatment goals for cystinuria are cystine concentration <250 mg/L, urine pH
>7.0. n/a, not available.

View Large


PATIENT 2

A 15-year-old girl developed severe abdominal pain, and renal ultrasound
revealed a large right kidney staghorn calculus and additional multiple stones
bilaterally. She underwent percutaneous nephrolithotomy of the right kidney and
started potassium citrate (10 mEq BID). Her stone was predominantly composed of
cystine, and she was diagnosed with cystinuria. She initially had low urine
volume (1.5 L per day) with good urine pH (7.5), normal urinary calcium (1.3
mg/kg per day), and low citrate excretion (307 mg/g creatinine); however, the
cystine parameters were not studied (Table 1). Potassium citrate was increased
to 45 mEq 3 times per day, and high fluid and low sodium intake was recommended.
Repeat 24-hour urine collection revealed improved urine volume (4.5 L), higher
urine pH (8.0) and citrate excretion (805 mg/g creatinine) with high cystine
excretion (628 mg per day), normal cystine supersaturation (0.35), and normal
cystine capacity (+290 mg/L). Potassium citrate was decreased to 45 mEq BID to
reduce alkalinization of urine to avoid calcium phosphate stone formation;
however, on this dose, normal levels could not be maintained for cystine
supersaturation (increased from 0.35 to 0.64) and cystine capacity (decreased
from +290 to +140 mg/L). Despite tripling her urine volume (1.5–4.5 L) and
increasing urine pH, she continued to have significant stone burden requiring
another percutaneous nephrolithotomy. She was deemed stone free at the end of
surgery, but she reported passing multiple stones 3 months later despite good
compliance. An ultrasound revealed new stones bilaterally (3 stones up to 9 mm
in the right kidney with mild hydronephrosis and one 4 mm stone in the left
kidney). ALA therapy (600 mg BID; 25 mg/kg per day or 840 mg/m2 per day) was
initiated, and after 1 month of treatment, urine cystine capacity almost doubled
(from +140 to +272 mg/L) and cystine supersaturation decreased (from 0.64 to
0.48) despite having lower urine volume (1.9 L); her potassium citrate dose was
further decreased to 30 mEq BID. An ultrasound performed 2 months after
initiating ALA therapy revealed only a 3-mm right nephrolith with resolution of
hydronephrosis. During the 5-month follow-up period, she reported not passing
any kidney stones, suggesting that ALA may have helped dissolution of existing
cystine stones; however, asymptomatic passage of stones could not be ruled out.


DISCUSSION

ALA is a nutritional supplement with a good safety profile. A 50% lethal dose of
ALA is >2000 mg/kg in rats. In animal studies, mild elevations in liver enzymes
were seen at very high ALA doses, and no significant toxicity was found after 24
months of treatment at lower doses.10,11  In humans, the side effects of ALA are
well documented in clinical trials for diabetic neuropathy. The most commonly
observed adverse effect was dose-dependent nausea, which affected 13% at 600 mg
per day, 21% at 1200 mg per day, and 48% at 1800 mg per day. Vomiting and
vertigo affected <5% of patients at 1200 mg per day.12  Our patients in this
report were treated with ALA at 600 to 1200 mg per day (on the basis of the
mouse dose in ref 9 ) and did not manifest any nausea, vomiting, or vertigo. We
monitored liver enzymes, serum creatinine, electrolytes, and hematologic indices
in both patients after 3 to 7 months of ALA treatment, which were within normal
range. Our findings are consistent with earlier studies revealing a good safety
profile for ALA in humans at this dosage.

The American Urological Association guidelines13  recommend the following for
medical management of cystine stones: increase fluid intake (usually >4 L),
dietary sodium and protein restriction, and urine alkalinization (pH >7.0) with
potassium citrate. In patients unresponsive to these measures, the American
Urological Association recommends using cystine-binding drugs. Serial 24-hour
urine tests are recommended to monitor urine volume, pH, cystine excretion,
cystine supersaturation, and cystine capacity. Cystine supersaturation is a
marker of cystine crystallization; it involves the measurement of cystine
concentration in urine before and after incubation with cystine crystals and is
calculated as the cystine concentration at baseline divided by the cystine
concentration after incubation. Supersaturation values <1.0 (suggesting urine is
undersaturated) are desired in patients with cystinuria.14  In patients using
cystine-binding drugs, cystine concentration and supersaturation become
unreliable because of the chemical interactions with cystine. Cystine capacity
is another parameter not affected by cystine-binding drugs, and positive values
are desired to prevent cystine stones.15  For capacity measurement, a known
amount of solid cystine is added to the patient’s urine, and after incubation,
solid cystine is recovered and quantified to compare to the original cystine
quantity. In supersaturated urine, cystine further precipitates onto added
crystals, and recovered solid cystine is greater than the added amount (ie,
negative cystine capacity). In undersaturated urine, the added solid cystine
partially dissolves; thus, recovered solid cystine is less than the added amount
(ie, positive cystine capacity).16  As seen in Table 1, patient 1 had high
cystine crystallization in her urine as suggested by high cystine
supersaturation (1.7) and low cystine capacity (−223 mg/L). Despite dietary
measures, increased fluid intake, and urine alkalinization, these parameters
remained unchanged. After ALA initiation, cystine supersaturation decreased to
1.09 and capacity increased to −62 mg/L with further improvements in cystine
supersaturation (<0.9) and capacity (almost 0) with increased ALA dose and
higher fluid intake. In patient 2, cystine supersaturation decreased from 0.64
to 0.48 and capacity increased from +140 to +272 mg/L with ALA treatment despite
lower urine volume (∼2 L); in the past, she could achieve similar
supersaturation and capacity values with only high urine volumes (∼4.5 L). Of
note, variability in creatinine, cystine and sodium excretions, urine pH
(despite citrate therapy), and protein catabolic rate (PCR) is a limitation of
our study likely due to variations in urine collections and diet. For instance,
patient 1 had a high PCR throughout the observation period, suggesting high
dietary protein intake, which can increase urinary cystine and calcium
excretion. In addition, daily urine volumes were variable in both patients
likely because of variations in collections (overcollection or undercollection,
as suggested by varying creatinine excretions) and/or variability in fluid
intake. However, these are well-known common limitations of 24-hour urine
collections in both adults and children,17,18  and the collection days do not
exactly reflect daily habits. Accurate urine collections are more challenging in
children and adolescents because of school attendance and other factors. Despite
these limitations, our results suggest therapeutic efficacy of ALA in both
patients. Our patients had no recurrence of stones on follow-up imaging, with
potential resolution of existing stones in one patient, and had resolution of
their symptoms, but clinical trials with larger number of patients are warranted
to systematically assess efficacy of ALA on urinary biochemical indices and
stone recurrence. Such a trial is ongoing in adult (≥18 years) patients with
cystinuria (www.clinicaltrials.gov [identifier: NCT02910531]). We believe our
report will open the way to start formal clinical trials for testing ALA in
pediatric patients with cystinuria, which is an important problem in children
because cystinuria often manifests in childhood (the mean age at first kidney
stone detection is 13 years).19 

The mechanism of action of ALA in cystinuria remains unknown. In the mouse
study, ALA treatment did not affect urine pH or cystine excretion; however, the
solubility of cystine was markedly increased in the urine of ALA-treated mice,9 
similar to our patients. Interestingly, when ALA was directly added to mouse
urine, it did not affect cystine solubility, suggesting the effect observed in
the mouse model was not due to direct action of ALA but likely due to the
metabolite(s) of ALA, which is yet to be determined.


CONCLUSIONS

We showed that ALA supplementation markedly improves the urinary markers of
cystine solubility in 2 pediatric patients with cystinuria with no associated
adverse effects. Considering its safety profile, clinicians may consider ALA
supplementation in patients refractory to conventional therapy and potentially
avoid using cystine-binding drugs that are associated with serious side effects.

Dr Cil developed the original idea and drafted the initial manuscript; and both
authors collected clinical data, reviewed and revised the manuscript, and
approved the final manuscript as submitted.

FUNDING: No external funding.

ALA

α-lipoic acid

BID

twice daily

PCR

protein catabolic rate


COMPETING INTERESTS

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no
potential conflicts of interest to disclose. Patients and parents were provided
detailed information about the potential side effects of cystine-binding drugs
versus α-lipoic acid, and after detailed discussions, they decided to use the
nutritional supplement α-lipoic acid. Patients and parents provided consent for
publication of medical information.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial
relationships relevant to this article to disclose


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Copyright © 2020 by the American Academy of Pediatrics
2020




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