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A-Lipoic Acid (ALA) Improves Cystine Solubility in Cystinuria: Report of 2 Cases Onur Cil, MD, Phd, Farzana Perwad, MD

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A-Lipoic Acid (ALA) Improves Cystine Solubility in Cystinuria: Report of 2 Cases Onur Cil, MD, Phd, Farzana Perwad, MD a-Lipoic Acid (ALA) Improves Cystine Solubility in Cystinuria: Report of 2 Cases Onur Cil, MD, PhD, Farzana Perwad, MD Cystinuria is an autosomal recessive disorder characterized by excessive abstract 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 a-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 Division of Pediatric Nephrology, Department of Pediatrics, University of California, San Francisco, San Francisco, potassium citrate. Both patients tolerated ALA without any adverse effects California and had reduced frequency of symptomatic and asymptomatic kidney stones Dr Cil developed the original idea and drafted the with disappearance of existing kidney stones in 1 patient after 2 months of initial manuscript; and both authors collected ALA therapy. ALA treatment markedly improved laboratory markers of clinical data, reviewed and revised the manuscript, cystine solubility in urine with increased cystine capacity (2223 to 21 mg/L and approved the final manuscript as submitted. in patient 1 and 1140 to 1272 mg/L in patient 2) and decreased DOI: https://doi.org/10.1542/peds.2019-2951 cystine supersaturation (1.7 to 0.88 in patient 1 and 0.64 to 0.48 in Accepted for publication Nov 7, 2019 patient 2) without any changes in cystine excretion or urine pH. Our findings Address correspondence to Onur Cil, MD, PhD, suggest that ALA improves solubility of cystine in urine and prevents stone Division of Pediatric Nephrology, Department of Pediatrics, University of California, San Francisco, formation in patients with cystinuria who do not respond to diet and citrate 550 16th St, San Francisco, CA 94158. E-mail: therapy. [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2020 by the American Academy of Cystinuria is an autosomal recessive in children. Potassium citrate is Pediatrics disorder characterized by increased frequently prescribed to alkalinize FINANCIAL DISCLOSURE: The authors have indicated urinary cystine excretion and recurrent urine and increase cystine solubility. they have no financial relationships relevant to this nephrolithiasis.1 Cystine stones often Reducing sodium and protein intake is article to disclose necessitate multiple procedures and/or also recommended to decrease cystine FUNDING: No external funding. 2 surgeries for removal, and patients excretion. Conservative measures (fluid POTENTIAL CONFLICT OF INTEREST: The authors have with cystinuria have higher incidence of and/or diet changes, citrate) frequently indicated they have no potential conflicts of interest chronic kidney disease compared to fail,5 and patients often require cystine- to disclose. Patients and parents were provided 3,4 detailed information about the potential side effects other stone formers. Urinary cystine binding drugs (D-penicillamine and a , of cystine-binding drugs versus -lipoic acid, and excretion is normally 30 mg per day tiopronin), which act by interfering after detailed discussions, they decided to use the 6 and is greatly increased (generally with cysteine dimerization. These nutritional supplement a-lipoic acid. Patients and .400 mg per day) in cystinuria. To drugs have variable efficacy and can parents provided consent for publication of medical keep urine cystine concentration below cause serious side effects such as information. the solubility limit (∼250 mg/L at pH nephrotic syndrome, hepatotoxicity, 7),5 patients with cystinuria often must and pancytopenia.7 There is a large To cite: Cil O and Perwad F. a-Lipoic Acid (ALA) have high urine output, which requires unmet need for safer and more Improves Cystine Solubility in Cystinuria: Report of 2 Cases. Pediatrics. 2020;145(5):e20192951 high fluid intake and can be challenging efficacious treatments for cystinuria. Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 145, number 5, May 2020:e20192951 CASE REPORT a-lipoic acid (ALA) is a dietary with a lower urine pH (7.2), and she (Table 1). Potassium citrate was supplement commonly used in was started on potassium citrate (0.5 increased to 45 mEq 3 times per day, diabetic neuropathy for its mEq/kg BID [twice daily]). Despite and high fluid and low sodium intake antioxidant effects.8 In a recent study, increased urine volume (1.1–1.3 L) was recommended. Repeat 24-hour authors reported efficacy of ALA and slightly higher urine pH (7.4) urine collection revealed improved (dose equivalent to ∼40 mg/kg per with citrate therapy, her cystine urine volume (4.5 L), higher urine pH day in humans) in preventing stone supersaturation and capacity (8.0) and citrate excretion (805 mg/g formation in a mouse model of remained unchanged in subsequent creatinine) with high cystine cystinuria.9 Here, we report use of urine analyses. She continued to have excretion (628 mg per day), normal ALA supplementation in 2 pediatric intermittent abdominal pain with no cystine supersaturation (0.35), and patients with cystinuria and stones detected on repeat ultrasound. normal cystine capacity (1290 mg/ demonstrate its efficacy in improving She was started on ALA L). Potassium citrate was decreased key urine markers of cystine supplementation (300 mg daily; to 45 mEq BID to reduce solubility (cystine supersaturation 17 mg/kg per day or ∼400 mg/m2 alkalinization of urine to avoid and capacity). per day) and continued using calcium phosphate stone formation; potassium citrate. After 1 month of however, on this dose, normal levels Urine tests for cystine solubility ALA treatment, there were could not be maintained for cystine were performed by Litholink substantial improvements in urine supersaturation (increased from 0.35 Corporation (Chicago, IL) as part of cystine capacity (from 2222 to to 0.64) and cystine capacity routine clinical care. Patients used 262 mg/L) and cystine (decreased from 1290 to 1140 mg/ 300- or 600-mg ALA capsules supersaturation (from 1.7 to 1.0). Her L). Despite tripling her urine volume manufactured by Natrol LLC (Los ALA dose was increased to 300 mg (1.5–4.5 L) and increasing urine pH, Angeles, CA). BID (34 mg/kg per day or ∼800 mg/ she continued to have significant m2 per day), and she started drinking stone burden requiring another CASE REPORT more water motivated by the percutaneous nephrolithotomy. She improvement in urine tests. Her most was deemed stone free at the end of Patient 1 recent 24-hour urine analysis surgery, but she reported passing A 6-year-old girl with a history of revealed further improvements in multiple stones 3 months later recurrent intermittent abdominal cystine supersaturation (0.88) and despite good compliance. An pain since 3 years of age was capacity (21 mg/L). She reported no ultrasound revealed new stones diagnosed with nephrolithiasis by adverse events with this therapy. bilaterally (3 stones up to 9 mm in renal ultrasound that revealed a 4- During the 11-month follow-up after the right kidney with mild mm left ureterovesical junction stone starting ALA, her episodes of hydronephrosis and one 4 mm stone with moderate abdominal pain completely resolved in the left kidney). ALA therapy hydroureteronephrosis. She and her surveillance ultrasounds (600 mg BID; 25 mg/kg per day or subsequently passed a 4-mm stone have not revealed any stones. 840 mg/m2 per day) was initiated, that was confirmed to be composed and after 1 month of treatment, urine Patient 2 of cystine by stone analysis and was cystine capacity almost doubled referred to the comprehensive A 15-year-old girl developed severe (from 1140 to 1272 mg/L) and pediatric kidney stone center at the abdominal pain, and renal ultrasound cystine supersaturation decreased University of California, San revealed a large right kidney staghorn (from 0.64 to 0.48) despite having Francisco. Her initial 24-hour urine calculus and additional multiple lower urine volume (1.9 L); her collection revealed low urine volume stones bilaterally. She underwent potassium citrate dose was further (0.75 L), high cystine excretion percutaneous nephrolithotomy of the decreased to 30 mEq BID. An (408 mg per day), high cystine right kidney and started potassium ultrasound performed 2 months after supersaturation (1.7) and low cystine citrate (10 mEq BID). Her stone was initiating ALA therapy revealed only capacity (2223 mg/L) with a pH of predominantly composed of cystine, a 3-mm right nephrolith with 7.44 (goal .7.0), and normal urinary and she was diagnosed with resolution of hydronephrosis. During calcium and citrate excretions cystinuria. She initially had low urine the 5-month follow-up period, she (Table 1). She was diagnosed with volume (1.5 L per day) with good reported not passing any kidney cystinuria and recommended to urine pH (7.5), normal urinary stones, suggesting that ALA may have increase fluid and limit sodium calcium (1.3 mg/kg per day), and low helped dissolution of existing cystine intake. Her follow-up 24-hour urine citrate excretion (307 mg/g stones; however, asymptomatic collection after 5 months revealed
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