Case Report: Cystinuria and Polycystic Kidney Disease Ajaydeep Sidhu, MD, a Angela Mittal, MD, b Xamayta Negroni-Balasquide, MD,c Alex Constantinescu, MD,c Kristin Kozakowski, MDb

Cystinuria and polycystic kidney disease are 2 genetic disorders that affect abstract the genitourinary tract but rarely together. This case report presents 2 pediatric patients diagnosed with polycystic kidney disease and cystinuria requiring surgical treatment. Both subjects presented acutely with stone disease. Imaging studies and stone analysis established the diagnoses. Although coexistence of these 2 conditions is rare, cystinuria should be considered in the differential diagnosis when evaluating patients with cystic disease who develop renal calculi.

a Mount Sinai Medical Center, Miami Beach, Florida; bNicklaus Children’s Hospital, Miami, Florida; and cJoe CASE REPORT completely encrusted with stone DiMaggio Children’s Hospital, Hollywood, Florida debris; he therefore required a Dr Sidhu drafted the initial manuscript and Patient A is now a 16-year-old male percutaneous nephrolithotomy researched the topic presented; Dr Mittal assisted from Honduras with a 6-year history (PCNL) for removal of the encrusted in drafting the initial manuscript, revised and of nephrolithiasis who originally fi nalized the manuscript, and was involved in stents. Lost to follow-up again, presented to our institution acutely in the surgical care of the patients presented; the patient presented acutely in September 2012 with a symptomatic Drs Negroni-Balasquide and Constantinescu November 2014 with a large stone reviewed and revised the manuscript and 2-mm left ureterovesical junction burden, including a 2.2 × 1.4 × 1.0 cm conceptualized the case report, as well as calculus. His medical history was left obstructing ureteropelvic junction provided the follow-up on the patients reported in notable for passing previous the article; Dr Kozakowski conceptualized the case calculus with hydronephrosis. His calculi at 10 years of age, and his report, took care of the patients surgically, and serum creatinine level at that time family history was notable for 3 revised the manuscript; and all authors approved was 0.91 mg/dL. He required 3 the fi nal manuscript as submitted. paternal uncles with nephrolithiasis. separate left PCNL procedures to Computed tomography scans of the DOI: 10.1542/peds.2016-0674 render his left collecting system stone- abdomen and pelvis without contrast Accepted for publication Aug 22, 2016 free. Stone analysis confirmed 100% demonstrated bilateral hypoechoic Address correspondence to Angela Mittal, MD, Texas cystine stone composition. The patient lesions consistent with renal cysts and Children's Hospital, Baylor College of Medicine, was referred to pediatric nephrology parenchymal calcifications consistent Suite D.0620.00 6701 Fannin St, Houston, TX 77030. and was started on tiopronin and E-mail: [email protected] with nephrocalcinosis. The imaging potassium citrate therapy, and an studies met the criteria for diagnosis PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, angiotensin-converting enzyme 1098-4275). of autosomal dominant polycystic inhibitor was eventually added for kidney disease (ADPKD), although Copyright © 2016 by the American Academy of hypertension. In May 2015, his serum Pediatrics his family history was unavailable. creatinine level was back down to His serum creatinine level was FINANCIAL DISCLOSURE: The authors have 0.76 mg/dL, and the renal ultrasound indicated they have no fi nancial relationships 0.76 mg/dL. The patient was treated at the time demonstrated bilateral relevant to this article to disclose. conservatively. Unfortunately, he was parenchymal calcifications without FUNDING: No external funding. lost to follow-up until 2013 when he hydronephrosis and multiple cysts. presented with a symptomatic 1-cm POTENTIAL CONFLICT OF INTEREST: The authors He does not have extrarenal cysts. have indicated they have no potential confl icts of left ureteropelvic junction stone with interest to disclose. hydronephrosis and a nonobstructing Patient B is now a 14-year-old female 1.1-cm right stone. He underwent who originally presented to urology bilateral ureteral stent placement for with a large left renal stone in January To cite: Sidhu A, Mittal A, Negroni-Balasquide X, radiolucent stones. At ureteroscopy 2012. She underwent an elective PCNL et al. Case Report: Cystinuria and Polycystic Kidney Disease. Pediatrics. 2016;138(6):e20160674 8 weeks later, both stents were and subsequent second-look PCNL

Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 138 , number 6 , December 2016 :e 20160674 CASE REPORT during the same admission to render and SLC7A9 on chromosome 2. In addition to poor compliance her left collecting system stone- SLC3A1 has an autosomal recessive with decreasing the urine cystine free. Stone analysis demonstrated inheritance, whereas SLC7A9 exhibits concentration, there are additional cystine calculi. Her serum creatinine variability in penetrance and clinical challenges with treating cystine level at the time was 0.76 mg/dL. presentation. 2 To our knowledge, calculi after they are formed. Pediatric nephrology started her there is no published evidence of Cystine stones tend to recur and are on tiopronin and potassium citrate. a genetic relationship between frequently bilateral. 7 Percutaneous A follow-up renal ultrasound in cystinuria and cystic renal disease. nephrolithotomy has been performed March 2014 demonstrated bilateral It is unclear if cystinuria will affect successfully in children with renal cysts, meeting the criteria the clinical course of ADPKD or vice substantial cystine stone burdens, for ADPKD; the patient also had a versa, as not many individuals have and it remains a mainstay for treating positive family history. A 24-hour both diagnoses. Further follow-up complex stones. Onal et al 8 achieved urinalysis demonstrated an of these patients could highlight any stone-free status in 63.1% of renal appropriate response to medical impact that either disease may have units (41 of 65 renal units) after therapy, based on cystine solubility. on the other. PCNL, which increased to nearly A follow-up ultrasound in January 74% after additional endoscopic 2015 demonstrated bilateral renal procedures. However, despite a Cystine solubility is highly cysts, with no evidence of extrarenal reasonable stone-free rate after dependent on urinary pH, cysteine cysts or recurrent stones. surgical treatment and subsequent concentration, and urinary continued medical treatment, macromolecules. Cystine crystallizes 31.2% of stone-free patients had a in physiologic urine, and cystine DISCUSSION recurrence; 29.4% of patients with solubility increases as pH increases. residual stone burden on medical ADPKD is the most common inherited Macromolecules (ie, colloid) also therapy experienced regrowth kidney disease and a common increase cystine solubility. Treatment despite medical therapy. These cause of end-stage renal disease of cystinuria typically focuses on patients should be closely monitored, in adults. Screening for ADPKD is increasing the urinary cystine as untreated cysteine stones may recommended for individuals with solubility through hydration, diet compromise kidney function further a strong family history and involves modification, urinary alkalinization, and faster in patients with ADPKD. imaging. The criteria for diagnosis in and/or the use of a chelating patients aged 15 to 39 years include agent. The typical goal is to lower Love and Yeo 9 previously reported at least 3 unilateral or bilateral cysts. the urine cystine concentration the finding of cystinuria in an adult Both of the presented patients fit to <250 to 300 mg/L to decrease patient with polycystic kidney these criteria according to results of stone formation. 3 – 5 In patients with disease. This 37-year-old patient imaging. Patients with ADPKD are heterozygote genotypes, the cysteine also had several renal parenchymal known to have an increased risk of concentration is significantly higher calcifications and was later found on nephrolithiasis, likely secondary to than in the normal population, but routine follow-up to have hexagonal- 1 both anatomic and metabolic factors. these individuals do not have a shaped crystals on urinalysis and However, cystine stones have rarely higher risk of stone formation, even was diagnosed with cystinuria. The been described in these patients. though the cysteine levels in the investigators postulate that this Cystinuria is a rare autosomal urine are high enough to theoretically combination of genetic diseases was recessive metabolic disease causing cause stones. This scenario indicates likely random. defective transepithelial amino acid that the current medical knowledge Koraishy et al 10 described a case transport in the kidneys. It results as it pertains to cystinuria is clearly of cystic kidney disease forming in an inability to reabsorb dibasic incomplete. Previous studies have in a patient who developed amino acids (cystine, ornithine, shown that overall compliance systemic toxicity from long-term lysine, and arginine) from the with cystinuria treatment and D-penicillamine use for cystinuria glomerular ultrafiltrate, resulting prevention can be poor. Pietrow treatment. Their patient presented in supersaturation and eventual et al 6 found that only 15% of patients for acute kidney injury while taking precipitation of cystine to form (4 of 26) at a mean follow-up of 38.2 D-penicillamine therapy and was calculi. months decreased urine cystine found to have severe bilateral ADPKD results from mutations concentration to a sustained level cystic kidney disease. In addition, in PKD1 on chromosome 16 and <300 mg/L. Without adequate the patient was found to have PKD2 on chromosome 4. Cystinuria treatment, patients rapidly develop other evidence of D-penicillamine arises from a mutation in SLC3A1 many stones. toxicity, including skin findings.

Downloaded from www.aappublications.org/news by guest on October 2, 2021 e2 SIDHU et al D-penicillamine is known to result access may be changed, based on the contemporary clinical practice. J Urol. in improper collagen deposition and location of the cysts, to avoid them if 1996;156(5):1576–1578 function of elastic fibers. The authors possible; ultimately, the access route 4. Barbey F, Joly D, Rieu P, Méjean postulated that D-penicillamine will depend on the interventionalist. A, Daudon M, Jungers P. Medical use produced dysfunction of the This article describes the first treatment of cystinuria: critical extracellular matrix, eventually cases of coexistent ADPKD and reappraisal of long-term results. J Urol. 2000;163(5):1419–1423 resulting in cyst formation. Of note, cystinuria reported in children neither of our patients was taking and suggests evaluation for the 5. Joly D, Rieu P, Méjean A, Gagnadoux D-penicillamine, or any therapy for possibility of cystine stones in MF, Daudon M, Jungers P. Treatment cystinuria, when they presented. patients with ADPKD presenting with of cystinuria. Pediatr Nephrol. ADPKD does not affect the ability nephrolithiasis. 1999;13(9):945–950 to perform purely endoscopic 6. Pietrow P, Auge BK, Weizer AZ, et al. procedures on patients with Durability of the medical management stone disease. Ureteroscopy, laser ABBREVIATIONS of cystinuria. J Urol. 2003;169(1):68–70 lithotripsy, and basket extraction ADPKD: autosomal dominant 7. Knoll T, Zöllner A, Wendt-Nordahl of stones is not different in these polycystic kidney disease G, Michel MS, Alken P. Cystinuria patients because the calyces and PCNL: percutaneous nephrolitho- in childhood and adolescence: the ureter are not affected by the tomy recommendations for diagnosis, ADPKD. Many cystine stones are very treatment, and follow-up. Pediatr large and necessitate percutaneous Nephrol. 2005;20(1):19–24 nephrolithotomy, which requires REFERENCES 8. Onal B, Dogan C, Citgez S, et al. percutaneous access through the 1. Grampsas SA, Chandhoke PS, Fan J, Percutaneous nephrolithotomy in kidney parenchyma. This access et al. Anatomic and metabolic risk children with cystine stone: long-term can be more difficult in patients factors for nephrolithiasis in patients outcomes from a single institution. with ADPKD and will depend on the with autosomal dominant polycystic J Urol. 2013;190(1):234–237 relative enlargement of the kidney, kidney disease. Am J Kidney Dis. 9. Love K, Yeo FE. Cystinuria in a patient the location of cysts, and if the cysts 2000;36(1):53–57 with polycystic kidney disease. NDT are distorting the calyces. Larger 2. Eggermann T, Venghaus A, Zerres Plus. 2009;2(1):30–33 kidneys will require longer access K. Cystinuria: an inborn cause of 10. Koraishy FM, Cohen RA, Israel GM, Dahl needles, and distorted calyces will urolithiasis. Orphanet J Rare Dis. NK. Cystic kidney disease in a patient make it harder for the radiologist 2012;7:19 with systemic toxicity from long-term or the urologist to gain access to the 3. Chow GK, Streem SB. Medical D-penicillamine use. Am J Kidney Dis. collecting system. The course of the treatment of cystinuria: results of 2013;62(4):806–809

Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 138 , number 6 , December 2016 e3 Case Report: Cystinuria and Polycystic Kidney Disease Ajaydeep Sidhu, Angela Mittal, Xamayta Negroni-Balasquide, Alex Constantinescu and Kristin Kozakowski Pediatrics originally published online November 15, 2016;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2016/11/11/peds.2 016-0674 References This article cites 10 articles, 0 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2016/11/11/peds.2 016-0674#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Nephrology http://www.aappublications.org/cgi/collection/nephrology_sub Urology http://www.aappublications.org/cgi/collection/urology_sub Genitourinary Disorders http://www.aappublications.org/cgi/collection/genitourinary_disorder s_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on October 2, 2021 Case Report: Cystinuria and Polycystic Kidney Disease Ajaydeep Sidhu, Angela Mittal, Xamayta Negroni-Balasquide, Alex Constantinescu and Kristin Kozakowski Pediatrics originally published online November 15, 2016;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2016/11/11/peds.2016-0674

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2016 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Downloaded from www.aappublications.org/news by guest on October 2, 2021