View source for Cystinuria

{{Short description|Disease of the kidneys, ureter, and bladder}}
{{Medref|date=July 2020}}
{{Infobox medical condition (new)
| name            = Cystinuria
| image           = Cystine Crystals in Canine Urine Sediment.jpg
| caption         = These cystine crystals were found in the urine sediment of a male dog who presented to the veterinary hospital with a history of chronic stranguria (straining to urinate) and pollakiuria (abnormally increased frequency of urination).  A cystotomy was performed and numerous cystoliths (bladder stones) were removed.  5μm scale bar; 1,000x magnification; focus-stacked image consisting of 12 exposures; courtesy of Lance Wheeler.
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| synonyms        =  Cystinuria-lysinuria<ref name=rarediseases>{{cite web |title=Cystinuria {{!}} Genetic and Rare Diseases Information Center (GARD) – an NCATS Program |url=https://rarediseases.info.nih.gov/diseases/6237/disease |website=rarediseases.info.nih.gov |access-date=15 April 2019 |archive-date=15 April 2019 |archive-url=https://web.archive.org/web/20190415224645/https://rarediseases.info.nih.gov/diseases/6237/disease |url-status=dead }}</ref>
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'''Cystinuria''' is an inherited [[Genetic disorder#Autosomal recessive|autosomal recessive disease]]<ref name=rarediseases/> characterized by high [[concentration]]s of the amino acid [[cystine]] in the [[urine]], leading to the formation of cystine [[kidney stone disease|stones]] in the [[kidney]]s, [[ureter]]s, and [[urinary bladder|bladder]]. It is a type of [[aminoaciduria]]. "Cystine", not "cysteine," is implicated in this disease; the former is a [[Dimer (chemistry)|dimer]] of the latter.

==Presentation==
Cystinuria is a cause of recurrent kidney stones.  It is a disease involving the defective transepithelial transport of cystine and dibasic amino acids in the kidney and intestine and is one of many causes of kidney stones. If not treated properly, the disease could cause serious damage to the kidneys and surrounding organs, and in some rare cases death.  The stones may be identified by a positive [[nitroprusside cyanide]] test. The crystals are usually hexagonal, translucent, and white. Upon removal, the stones may be pink or yellow, but later they turn greenish due to exposure to air. Cystinuria is usually asymptomatic when no stone is formed. However, once a stone is formed, signs and symptoms can occur:<ref name=rarediseases/>
* Nausea
* Flank pain
* [[Hematuria]]
* [[Urinary tract infection]]s
* Rarely, [[acute kidney injury|acute]] or [[chronic kidney disease]]

People with cystinuria pass stones monthly, weekly, or daily, and need ongoing care. Cystinurics have an increased risk for [[chronic kidney disease]]<ref>{{cite journal |pages=2069–75 |doi=10.2215/CJN.10651110 |pmc=3156433 |title=Chronic Kidney Disease in Kidney Stone Formers |year=2011 |last1=Rule |first1=A. D. |last2=Krambeck |first2=A. E. |last3=Lieske |first3=J. C. |journal=Clinical Journal of the American Society of Nephrology |volume=6 |issue=8 |pmid=21784825}}</ref><ref>{{cite journal |pages=804–11 |doi=10.2215/CJN.05811108 |pmc=2666438 |title=Kidney Stones and the Risk for Chronic Kidney Disease |year=2009 |last1=Rule |first1=A. D. |last2=Bergstralh |first2=E. J. |last3=Melton |first3=L. J. |last4=Li |first4=X. |last5=Weaver |first5=A. L. |last6=Lieske |first6=J. C. |journal=Clinical Journal of the American Society of Nephrology |volume=4 |issue=4 |pmid=19339425}}</ref> and since kidney damage or poor function is often present in people with cystinuria, [[nonsteroidal anti-inflammatory drug]]s (NSAIDs) or over the counter (OTC) medications should be used with caution.

Cystine stones are often difficult to detect using plain X-rays. [[Computed tomography]] or [[ultrasound]] may be used instead for imaging.<ref>{{cite web |last1=Shah |first1=Sorvin M. |title=Cystinuria: MedlinePlus Medical Encyclopedia |url=https://medlineplus.gov/ency/article/000346.htm |website=medlineplus.gov |access-date=4 January 2021 |language=en |date=15 January 2020}}</ref>

Urine odor in cystinuria smells of rotten eggs due to the increase in cystine.<ref name=Biyani>{{cite journal|vauthors=Biyani CS, Cartledge JJ|title=Cystinuria—Diagnosis and Management|journal=EAU-EBU Update Series|volume=4|issue=5|year=2006|pages=175–83|issn=1871-2592|doi=10.1016/j.eeus.2006.06.001|url=http://eu-acme.org/europeanurology/upload_articles/Cystinuria.pdf|access-date=2015-04-21|archive-url=https://web.archive.org/web/20160305012710/http://eu-acme.org/europeanurology/upload_articles/Cystinuria.pdf|archive-date=2016-03-05|url-status=dead}}</ref>

==Genetics==
[[Image:Autosomal recessive - en.svg|thumb|left|Cystinuria has an autosomal recessive pattern of [[heredity|inheritance]].]]
Cystinuria is an autosomal recessive disease,<ref name=rarediseases/> which means that the defective gene responsible for the disease is located on an [[autosome]], and two copies of the defective gene (one inherited from each parent) are required to be born with the disease. The parents of an individual with an autosomal recessive disease both [[genetic carrier|carry]] one copy of the defective gene, but usually do not experience any signs or symptoms of the disease. Although signs and symptoms are rare, there are some directly and indirectly associated with cystinuria. These signs and symptoms consist of 1) hematuria- blood in the urine, 2) flank pain – pain in the side due to kidney pain, 3) renal colic – intense, cramping pain due to stones in the urinary tract, 4) obstructive uropathy- urinary tract disease due to obstruction, and 5) urinary tract infections.{{cn|date=September 2021}}

===Cause===
Cystinuria is caused by mutations in the ''[[SLC3A1]]'' and ''[[SLC7A9]]'' genes.  These defects prevent proper reabsorption of basic, or positively charged, amino acids: [[cystine]],  [[lysine]], [[ornithine]], [[arginine]].<ref>{{cite journal |pages=799–801 |doi=10.1136/pgmj.2005.044156 |pmc=2653923 |title=Cystine calculi: Challenging group of stones |year=2006 |last1=Ahmed |first1=K. |last2=Dasgupta |first2=P. |last3=Khan |first3=M. S. |journal=Postgraduate Medical Journal |volume=82 |issue=974 |pmid=17148700}}</ref> Under normal circumstances, this protein allows certain amino acids, including cystine, to be reabsorbed into the blood from the filtered fluid that will become urine. Mutations in either of these genes disrupt the ability of this transporter protein to reabsorb these amino acids, allowing them to become concentrated in the urine. As the levels of cystine in the urine increase, it forms [[cystine]] crystals, resulting in kidney stones.  Cystine crystals form hexagonal-shaped crystals that can be viewed upon microscopic analysis of the urine.  The other amino acids that are not reabsorbed do not create crystals in urine.{{cn|date=September 2021}}

The overall [[prevalence]] of cystinuria is approximately 1 in 7,000 neonates (from 1 in 2,500 neonates in [[Libyan]] [[Jew]]s to 1 in 100,000 among [[Swedes]]).<ref name="omim">{{OMIM|220100}}</ref>

==Pathophysiology==
Cystinuria is characterized by the inadequate reabsorption of cystine in the proximal convoluted tubules after the filtering of the amino acids by the kidney's glomeruli, thus resulting in an excessive concentration of this [[amino acid]] in the urine.  Cystine may [[precipitate]] out of the [[urine]], if the urine is [[pH|neutral or acidic]], and form [[crystal]]s or stones in the kidneys, ureters, or bladder. It is one of several [[inborn errors of metabolism]] included in the [[Garrod's tetrad]]. The disease is attributed to a deficiency in the transport and metabolism of amino acids.{{cn|date=September 2021}}

==Diagnosis==

# Blood: Routine [[hemogram]] along with blood sugar, urea, and creatinine.
# Urine: For cystine crystals, and casts. The most specific test is the cyanide–nitroprusside test
# Ultrasound/CT scan to reveal if a stone is present.
# Genetic analysis to determine which mutation associated with the disease may be present. Currently genotyping is not available in the United States but might be available in Spain, Italy, the UK, Germany, and Russia (by private companies in Germany and Russia).

Regular X-rays often fail to show the cystine stones, however, they can be visualized in the diagnostic procedure that is called [[intravenous pyelogram]] (IVP). Stones may show up on XR with a fuzzy gray appearance.  They are radioopaque due to sulfur content, though more difficult to visualize than calcium oxalate stones.{{cn|date=September 2021}}

==Treatment==
Initial treatment is with adequate hydration, alkalization of the urine with citrate supplementation or acetazolamide, and dietary modification to reduce salt and protein intake (especially [[methionine]]). If this fails then patients are usually started on [[chelation therapy]] with an agent such as [[penicillamine]].<ref>{{cite journal |pages=141–4 |doi=10.1159/000112603 |title=Management of Cystinuric Patients: An Observational, Retrospective, Single-Centre Analysis |year=2008 |last1=Ahmed |first1=Kamran |last2=Khan |first2=Mohammad Shamim |last3=Thomas |first3=Kay |last4=Challacombe |first4=Ben |last5=Bultitude |first5=Matthew |last6=Glass |first6=Jonathan |last7=Tiptaft |first7=Richard |last8=Dasgupta |first8=Prokar |journal=Urologia Internationalis |volume=80 |issue=2 |pmid=18362482|s2cid=719486 }}</ref><ref name="pmid10603157">{{cite journal |pages=945–50  |doi=10.1007/s004670050736 |title=Treatment of cystinuria |year=1999 |last1=Joly |first1=Dominique |last2=Rieu |first2=Philippe |last3=méJean |first3=Arnaud |last4=Gagnadoux |first4=Marie-France |last5=Daudon |first5=Michel |last6=Jungers |first6=P. |journal=Pediatric Nephrology |volume=13 |issue=9 |pmid=10603157|s2cid=20984151 }}</ref> [[Tiopronin]] is another agent.
Once renal stones have formed, however, the first-line treatment is endoscopic laser lithotripsy. ESWL ([[Extracorporeal shock wave lithotripsy]]) is often not effective because of the hardness of the stones that do not fragment easily. Conventional open-abdominal surgery is rarely used but has proven to be an effective treatment modality for patients with more advanced forms of the disease. Adequate hydration is the foremost aim of treatment to prevent cystine stones. The goal is to increase the urine volume because the concentration of cystine in the urine is reduced which prevents cystine from precipitating from the urine and forming stones. People with cystine stones should consume 5 to 7 liters a day. The rationale behind alkalizing the urine is that cystine tends to stay in solution and causes no harm. To alkalinize the urine, sodium bicarbonate has been used. One must be careful in alkalizing their urine because it could lead to other forms of stones in the process of preventing cystine stones.  Penicillamine is a drug that acts to form a complex with cystine that is 50 times more soluble than cystine itself. Percutaneous nephrolithotripsy (PNL) is performed via a port created by puncturing the kidney through the skin and enlarging the access port to 1&nbsp;cm in diameter.  Most of the time, cystine stones are too dense to be broken up by shock (ESWL) so PNL is needed.{{cn|date=September 2021}}

Videos of surgery are available on various websites that show stone removal by percutaneous nephrolithotomy.{{cn|date=September 2021}}

In February 2017, an article was published in ''Nature Medicine'' entitled "Alpha lipoic acid treatment prevents cystine urolithiasis in a mouse model of cystinuria", suggesting that a high dose of the readily available antioxidant, alpha-lipoic acid at 2,700&nbsp;mg/67&nbsp;kg body weight daily reduced the incidence of stones. The effects were dose dependent.<ref>{{Cite journal|last1=Zee|first1=Tiffany|last2=Bose|first2=Neelanjan|last3=Zee|first3=Jarcy|last4=Beck|first4=Jennifer N.|last5=Yang|first5=See|last6=Parihar|first6=Jaspreet|last7=Yang|first7=Min|last8=Damodar|first8=Sruthi|last9=Hall|first9=David|date=March 2017|title=α-Lipoic acid treatment prevents cystine urolithiasis in a mouse model of cystinuria|journal=Nature Medicine|language=en|volume=23|issue=3|pages=288–290|doi=10.1038/nm.4280|pmid=28165480|issn=1078-8956|pmc=5656064}}</ref> The results are unprecedented for cystinuria.<ref name="ScienceDaily">{{Cite news|url=https://www.sciencedaily.com/releases/2017/02/170206111926.htm|title=Alpha-lipoic acid prevents kidney stones in mouse model of rare genetic disease: Research leads to clinical trial for cystinuria|work=ScienceDaily|access-date=2017-07-09|language=en}}</ref> A clinical trial is underway based on this mouse model.<ref name="ScienceDaily"/>

== Occurrence in animals ==
This disease is known to occur in at least four [[mammal]]ian species: [[human]]s, domestic [[dog|canines]], domestic ferrets, and a wild canid, the [[maned wolf]] of [[South America]].
Cystine uroliths have been demonstrated, usually in male dogs, from approximately 70 breeds including the Australian cattle dog, Australian shepherd, Basenji, Basset, Bullmastiff, Chihuahua, Scottish deerhound, Scottish terrier, Staffordshire terrier, Welsh corgi, and [[Newfoundland dog]]s.<ref>{{cite journal |doi=10.1016/j.cvsm.2008.09.006 |author1=D Bannasch |author2=PS Henthorn |title=Changing Paradigms in Diagnosis of Inherited Defects Associated with Uroliths|journal=Veterinary Clinics of North America: Small Animal Practice|volume=39|issue=1|pages=111–125 |year=2009 |pmid=19038654 |pmc=2628803}}</ref>

==See also==
{{col div|colwidth=40em}}
* [[Cystine]]
* [[Cysteine]]
* [[Tiopronin]]
* [[International Cystinuria Foundation]]
* [[Hartnup disease]]
* [[Cystinosis]]
* [[Homocystinuria]]
* [[Medullary sponge kidney]]
{{colend}}

==References==
{{reflist}}

== External links ==
{{Medical resources
|   DiseasesDB     = 3339
|   ICD10          = {{ICD10|E|72|0|e|70}}
|   ICD9           = {{ICD9|270.0}}
|   ICDO           =
|   OMIM           = 220100
|   MedlinePlus    = 000346
|   eMedicineSubj  = med
|   eMedicineTopic = 498
|   MeshID         = D003555
}}
{{Amino acid metabolic pathology}}
{{Membrane transport protein disorders}}

[[Category:Amino acid metabolism disorders]]
[[Category:Autosomal recessive disorders]]
[[Category:Membrane transport protein disorders]]