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 to reduce cystine excretion and/or increase solubility. and D- 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 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 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 creatinine); however, the cystine passage of stones could not be hypercalciuria (7.9 mg/kg per day) parameters were not studied ruled out.

Downloaded from www.aappublications.org/news by guest on September 24, 2021 2 CIL and PERWAD TABLE 1 Twenty-four–Hour Urine Parameters of Patient 1 and 2 Before and After ALA Therapy Treatment Urine Urine Cystine Cystine Cystine Creatinine Calcium Citrate PCR, Sodium Volume, pH Excretion, Supersaturation Capacity, Excretion, Excretion, Excretion, g/kg Excretion, L/d mg/d mg/L mg/kg per d mg/kg per d mg/g per d mmol/d Creatinine Patient 1 Baseline 0.75 7.44 408 1.7 2223 21.6 3.4 1036 1.8 78 Baseline 1.28 7.20 632 1.63 2226 23.1 7.9 1135 2.6 71 Potassium 1.08 7.39 630 1.7 2222 21.8 4.6 1218 2.1 79 citrate Potassium 1.42 7.53 464 1.09 262 18.9 5.4 1251 1.6 45 citrate 1 lower-dose ALA Potassium 2.13 7.31 587 0.88 21 19.2 8.1 1324 2.3 99 citrate 1 higher-dose ALA Patient 2 Low-dose 1.5 7.57 n/a n/a n/a 27.6 1.3 307 n/a 146 Potassium citrate High-dose 4.55 8.0 623 0.35 294 27.5 1.1 805 1.0 145 Potassium citrate Moderate-dose 4.5 7.76 662 0.47 145 21.3 0.6 592 0.9 105 Potassium citrate Moderate-dose 2.87 7.80 700 0.64 140 21.5 1.0 664 0.9 122 Potassium citrate Moderate-dose 1.96 7.98 545 0.48 272 18.9 0.7 664 0.7 62 Potassium citrate 1 ALA Treatment goals for cystinuria are cystine concentration ,250 mg/L, urine pH .7.0. n/a, not available.

DISCUSSION not manifest any nausea, vomiting, or drugs. Serial 24-hour urine tests are ALA is a nutritional supplement with vertigo. We monitored liver enzymes, recommended to monitor urine a good safety profile. A 50% lethal serum creatinine, electrolytes, and volume, pH, cystine excretion, cystine dose of ALA is .2000 mg/kg in rats. hematologic indices in both patients supersaturation, and cystine capacity. In animal studies, mild elevations in after 3 to 7 months of ALA Cystine supersaturation is a marker liver enzymes were seen at very high treatment, which were within normal of cystine crystallization; it involves ALA doses, and no significant toxicity range. Our findings are consistent the measurement of cystine was found after 24 months of with earlier studies revealing a good concentration in urine before and treatment at lower doses.10,11 In safety profile for ALA in humans at after incubation with cystine crystals humans, the side effects of ALA are this dosage. and is calculated as the cystine well documented in clinical trials for concentration at baseline divided by diabetic neuropathy. The most The American Urological Association the cystine concentration after 13 commonly observed adverse effect guidelines recommend the incubation. Supersaturation values was dose-dependent nausea, which following for medical management of ,1.0 (suggesting urine is affected 13% at 600 mg per day, 21% cystine stones: increase fluid intake undersaturated) are desired in at 1200 mg per day, and 48% at (usually .4 L), dietary sodium and patients with cystinuria.14 In 1800 mg per day. Vomiting and protein restriction, and urine patients using cystine-binding drugs, vertigo affected ,5% of patients at alkalinization (pH .7.0) with cystine concentration and 1200 mg per day.12 Our patients in potassium citrate. In patients supersaturation become unreliable this report were treated with ALA at unresponsive to these measures, the because of the chemical interactions 600 to 1200 mg per day (on the basis American Urological Association with cystine. Cystine capacity is of the mouse dose in ref 9) and did recommends using cystine-binding another parameter not affected by

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 145, number 5, May 2020 3 cystine-binding drugs, and positive (overcollection or undercollection, as CONCLUSIONS values are desired to prevent cystine suggested by varying creatinine We showed that ALA 15 fl stones. For capacity measurement, excretions) and/or variability in uid supplementation markedly improves a known amount of solid cystine is intake. However, these are well- the urinary markers of cystine ’ added to the patient s urine, and after known common limitations of 24- solubility in 2 pediatric patients with incubation, solid cystine is recovered hour urine collections in both adults cystinuria with no associated adverse fi 17,18 and quanti ed to compare to the and children, and the collection effects. Considering its safety profile, fl original cystine quantity. In days do not exactly re ect daily clinicians may consider ALA supersaturated urine, cystine further habits. Accurate urine collections are supplementation in patients precipitates onto added crystals, and more challenging in children and refractory to conventional recovered solid cystine is greater than adolescents because of school therapy and potentially avoid the added amount (ie, negative attendance and other factors. using cystine-binding drugs cystine capacity). In undersaturated Despite these limitations, our that are associated with serious urine, the added solid cystine results suggest therapeutic side effects. partially dissolves; thus, recovered efficacy of ALA in both solid cystine is less than the added patients. Our patients had no amount (ie, positive cystine recurrence of stones on follow-up ABBREVIATIONS capacity).16 As seen in Table 1, imaging, with potential resolution of a patient 1 had high cystine existing stones in one patient, and ALA: -lipoic acid crystallization in her urine as had resolution of their symptoms, but BID: twice daily suggested by high cystine clinical trials with larger number of PCR: protein catabolic rate supersaturation (1.7) and low cystine patients are warranted to capacity (2223 mg/L). Despite systematically assess efficacy of ALA dietary measures, increased fluid on urinary biochemical indices and intake, and urine alkalinization, these stone recurrence. Such a trial is REFERENCES $ parameters remained unchanged. ongoing in adult ( 18 years) patients 1. Sahota A, Tischfield JA, Goldfarb DS, After ALA initiation, cystine with cystinuria (www.clinicaltrials. Ward MD, Hu L. Cystinuria: genetic supersaturation decreased to 1.09 gov [identifier: NCT02910531]). 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Downloaded from www.aappublications.org/news by guest on September 24, 2021 α-Lipoic Acid (ALA) Improves Cystine Solubility in Cystinuria: Report of 2 Cases Onur Cil and Farzana Perwad Pediatrics originally published online April 3, 2020;

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