Cystinuria

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Cystinuria
Other namesCystinuria-lysinuria [1]
Cystine Crystals in Canine Urine Sediment.jpg
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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Cystinuria is an inherited autosomal recessive disease [1] characterized by high concentrations of the amino acid cystine in the urine, leading to the formation of cystine stones in the kidneys, ureters, and bladder. It is a type of aminoaciduria. "Cystine", not "cysteine," is implicated in this disease; the former is a dimer of the latter.

Contents

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, white. Upon removal, the stones may be pink or yellow in color, but later they turn to 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: [1]

People with cystinuria pass stones monthly, weekly, or daily, and need ongoing care. Cystinurics have an increased risk for chronic kidney disease [2] [3] and since kidney damage or poor function is often present in cystinurics, the use of nonsteroidal anti-inflammatory drugs (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. [4]

Urine odor in cystinuria has a smell of rotten eggs due to the increase in cystine. [5]

Genetics

Cystinuria has an autosomal recessive pattern of inheritance. Autosomal recessive - en.svg
Cystinuria has an autosomal recessive pattern of inheritance.

Cystinuria is an autosomal recessive disease, [1] 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 in order to be born with the disease. The parents of an individual with an autosomal recessive disease both 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 sign 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.[ citation needed ]

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. [6] 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.[ citation needed ]

The overall prevalence of cystinuria is approximately 1 in 7,000 neonates (from 1 in 2,500 neonates in Libyan Jews to 1 in 100,000 among Swedes). [7]

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 neutral or acidic, and form crystals 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 deficiency in transport and metabolism of amino acids.[ citation needed ]

Diagnosis

  1. Blood: Routine hemogram along with blood sugar, urea, and creatinine.
  2. Urine: For cystine crystals, and casts. The most specific test is the cyanide–nitroprusside test
  3. Ultrasound/CT scan to reveal if a stone is present.
  4. 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, 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.[ citation needed ]

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. [8] [9] 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 effective treatment modalities for patients with more advanced 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. In order to alkalize 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 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 cm in diameter. Most of the time, cystine stones are too dense to be broken up by shock (ESWL) so PNL is needed.[ citation needed ]

Videos of surgery are available on various websites that show stone removal by percutaneous nephrolithotomy.[ citation needed ]

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 mg/67 kg body weight daily reduced the incidence of stones. The effects were dose dependent. [10] The results are unprecedented for cystinuria. [11] A clinical trial is underway based on this mouse model. [11]

Occurrence in animals

This disease is known to occur in at least four mammalian species: humans, domestic 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 both male and female Newfoundland dogs. [12]

See also

Related Research Articles

<span class="mw-page-title-main">Kidney</span> Vertebrate organ that filters blood and produces urine

The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about 12 centimetres in length. They receive blood from the paired renal arteries; blood exits into the paired renal veins. Each kidney is attached to a ureter, a tube that carries excreted urine to the bladder.

<span class="mw-page-title-main">Kidney stone disease</span> Formation of mineral stones in the urinary tract

Kidney stone disease, also known as nephrolithiasis or urolithiasis, is a crystallopathy where a solid piece of material develops in the urinary tract. Kidney stones typically form in the kidney and leave the body in the urine stream. A small stone may pass without causing symptoms. If a stone grows to more than 5 millimeters, it can cause blockage of the ureter, resulting in sharp and severe pain in the lower back or abdomen. A stone may also result in blood in the urine, vomiting, or painful urination. About half of people who have had a kidney stone will have another within ten years.

The excretory system is a passive biological system that removes excess, unnecessary materials from the body fluids of an organism, so as to help maintain internal chemical homeostasis and prevent damage to the body. The dual function of excretory systems is the elimination of the waste products of metabolism and to drain the body of used up and broken down components in a liquid and gaseous state. In humans and other amniotes most of these substances leave the body as urine and to some degree exhalation, mammals also expel them through sweating.

<span class="mw-page-title-main">Bladder stone</span> Concretion of material in the urinary bladder

A bladder stone is a stone found in the urinary bladder.

<span class="mw-page-title-main">Cystinosis</span> Lysosomal storage disease

Cystinosis is a lysosomal storage disease characterized by the abnormal accumulation of cystine, the oxidized dimer of the amino acid cysteine. It is a genetic disorder that follows an autosomal recessive inheritance pattern. It is a rare autosomal recessive disorder resulting from accumulation of free cystine in lysosomes, eventually leading to intracellular crystal formation throughout the body. Cystinosis is the most common cause of Fanconi syndrome in the pediatric age group. Fanconi syndrome occurs when the function of cells in renal tubules is impaired, leading to abnormal amounts of carbohydrates and amino acids in the urine, excessive urination, and low blood levels of potassium and phosphates.

<span class="mw-page-title-main">Gitelman syndrome</span> Medical condition

Gitelman syndrome (GS) is an autosomal recessive kidney tubule disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. The disorder is caused by genetic mutations resulting in improper function of the thiazide-sensitive sodium-chloride symporter located in the distal convoluted tubule of the kidney. The distal convoluted tubule of the kidney plays an important homoestatic role in sodium and chloride absorption as well as of the reabsorption of magnesium and calcium.

<span class="mw-page-title-main">Potassium citrate</span> Chemical compound

Potassium citrate (also known as tripotassium citrate) is a potassium salt of citric acid with the molecular formula K3C6H5O7. It is a white, hygroscopic crystalline powder. It is odorless with a saline taste. It contains 38.28% potassium by mass. In the monohydrate form, it is highly hygroscopic and deliquescent.

<span class="mw-page-title-main">Hartnup disease</span> Metabolic disorder

Hartnup disease is an autosomal recessive metabolic disorder affecting the absorption of nonpolar amino acids. Niacin is a precursor to nicotinamide, a necessary component of NAD+.

<span class="mw-page-title-main">Crystalluria</span> Medical condition

Crystalluria refers to crystals found in the urine when performing a urine test. Crystalluria is considered often as a benign condition and as one of the side effects of sulfonamides and penicillins.

<span class="mw-page-title-main">Bladder stone (animal)</span>

Bladder stones or uroliths are a common occurrence in animals, especially in domestic animals such as dogs and cats. Occurrence in other species, including tortoises, has been reported as well. The stones form in the urinary bladder in varying size and numbers secondary to infection, dietary influences, and genetics. Stones can form in any part of the urinary tract in dogs and cats, but unlike in humans, stones of the kidney are less common and do not often cause significant disease, although they can contribute to pyelonephritis and chronic kidney disease. Types of stones include struvite, calcium oxalate, urate, cystine, calcium phosphate, and silicate. Struvite and calcium oxalate stones are by far the most common.

<span class="mw-page-title-main">Dent's disease</span> Medical condition

Dent's disease is a rare X-linked recessive inherited condition that affects the proximal renal tubules of the kidney. It is one cause of Fanconi syndrome, and is characterized by tubular proteinuria, excess calcium in the urine, formation of calcium kidney stones, nephrocalcinosis, and chronic kidney failure.

Nephrocalcinosis, once known as Albright's calcinosis after Fuller Albright, is a term originally used to describe deposition of calcium salts in the renal parenchyma due to hyperparathyroidism. The term nephrocalcinosis is used to describe the deposition of both calcium oxalate and calcium phosphate. It may cause acute kidney injury. It is now more commonly used to describe diffuse, fine, renal parenchymal calcification in radiology. It is caused by multiple different conditions and is determined progressive kidney dysfunction. These outlines eventually come together to form a dense mass. During its early stages, nephrocalcinosis is visible on x-ray, and appears as a fine granular mottling over the renal outlines. It is most commonly seen as an incidental finding with medullary sponge kidney on an abdominal x-ray. It may be severe enough to cause renal tubular acidosis or even end stage kidney disease, due to disruption of the kidney tissue by the deposited calcium.

<span class="mw-page-title-main">Neutral and basic amino acid transport protein rBAT</span>

Neutral and basic amino acid transport protein rBAT is a protein that in humans is encoded by the SLC3A1 gene.

<span class="mw-page-title-main">Medullary sponge kidney</span> Congenital disorder of urinary system

Medullary sponge kidney is a congenital disorder of the kidneys characterized by cystic dilatation of the collecting tubules in one or both kidneys. Individuals with medullary sponge kidney are at increased risk for kidney stones and urinary tract infection (UTI). Patients with MSK typically pass twice as many stones per year as do other stone formers without MSK. While having a low morbidity rate, as many as 10% of patients with MSK have an increased risk of morbidity associated with frequent stones and UTIs. While many patients report increased chronic kidney pain, the source of the pain, when a UTI or blockage is not present, is unclear at this time. Renal colic is present in 55% of patients. Women with MSK experience more stones, UTIs, and complications than men. MSK was previously believed not to be hereditary but there is more evidence coming forth that may indicate otherwise.

Primary hyperoxaluria is a rare condition, resulting in increased excretion of oxalate, with oxalate stones being common.

<span class="mw-page-title-main">Djenkolic acid</span> Chemical compound

Djenkolic acid is a sulfur-containing non-protein amino acid naturally found in the djenkol beans of the Southeast Asian plant Archidendron jiringa. Its chemical structure is similar to cystine but contains a methylene unit in between the two sulfur atoms. There is about 20 grams of djenkolic acid per kilogram of dry djenkol beans, and it has also been reported in smaller amounts in the seeds of other leguminous plants such as Leucaena esculenta and Pithecolobium ondulatum.

<span class="mw-page-title-main">Polycystic kidney disease</span> Congenital disorder of urinary system

Polycystic kidney disease is a genetic disorder in which the renal tubules become structurally abnormal, resulting in the development and growth of multiple cysts within the kidney. These cysts may begin to develop in utero, in infancy, in childhood, or in adulthood. Cysts are non-functioning tubules filled with fluid pumped into them, which range in size from microscopic to enormous, crushing adjacent normal tubules and eventually rendering them non-functional as well.

<span class="mw-page-title-main">Distal renal tubular acidosis</span> Medical condition

Distal renal tubular acidosis (dRTA) is the classical form of RTA, being the first described. Distal RTA is characterized by a failure of acid secretion by the alpha intercalated cells of the distal tubule and cortical collecting duct of the distal nephron. This failure of acid secretion may be due to a number of causes. It leads to relatively alkaline urine, due to the kidney's inability to acidify the urine to a pH of less than 5.3.

<span class="mw-page-title-main">Tyrosinemia type I</span> Medical condition

Tyrosinemia type I is a genetic disorder that disrupts the metabolism of the amino acid tyrosine, resulting in damage primarily to the liver along with the kidneys and peripheral nerves. The inability of cells to process tyrosine can lead to chronic liver damage ending in liver failure, as well as renal disease and rickets. Symptoms such as poor growth and enlarged liver are associated with the clinical presentation of the disease. Clinical manifestation of disease occurs typically within the first two years of life. The severity of the disease is correlated with the timing of onset of symptoms, earlier being more severe.

Alkali citrate is an inhibitor of kidney stones. It is used to Increase urine citrate levels - this prevents calcium oxalate stones by binding to calcium and inhibiting its binding to oxalate. It is also used to increase urine pH - this prevents uric acid stones and cystine stones.

References

  1. 1 2 3 4 "Cystinuria | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Archived from the original on 15 April 2019. Retrieved 15 April 2019.
  2. ↑ Rule, A. D.; Krambeck, A. E.; Lieske, J. C. (2011). "Chronic Kidney Disease in Kidney Stone Formers". Clinical Journal of the American Society of Nephrology. 6 (8): 2069–75. doi:10.2215/CJN.10651110. PMC   3156433 . PMID   21784825.
  3. ↑ Rule, A. D.; Bergstralh, E. J.; Melton, L. J.; Li, X.; Weaver, A. L.; Lieske, J. C. (2009). "Kidney Stones and the Risk for Chronic Kidney Disease". Clinical Journal of the American Society of Nephrology. 4 (4): 804–11. doi:10.2215/CJN.05811108. PMC   2666438 . PMID   19339425.
  4. ↑ Shah, Sorvin M. (15 January 2020). "Cystinuria: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 4 January 2021.
  5. ↑ Biyani CS, Cartledge JJ (2006). "Cystinuria—Diagnosis and Management" (PDF). EAU-EBU Update Series. 4 (5): 175–83. doi:10.1016/j.eeus.2006.06.001. ISSN   1871-2592. Archived from the original (PDF) on 2016-03-05. Retrieved 2015-04-21.
  6. ↑ Ahmed, K.; Dasgupta, P.; Khan, M. S. (2006). "Cystine calculi: Challenging group of stones". Postgraduate Medical Journal. 82 (974): 799–801. doi:10.1136/pgmj.2005.044156. PMC   2653923 . PMID   17148700.
  7. ↑ Online Mendelian Inheritance in Man (OMIM): 220100
  8. ↑ Ahmed, Kamran; Khan, Mohammad Shamim; Thomas, Kay; Challacombe, Ben; Bultitude, Matthew; Glass, Jonathan; Tiptaft, Richard; Dasgupta, Prokar (2008). "Management of Cystinuric Patients: An Observational, Retrospective, Single-Centre Analysis". Urologia Internationalis. 80 (2): 141–4. doi:10.1159/000112603. PMID   18362482. S2CID   719486.
  9. ↑ Joly, Dominique; Rieu, Philippe; méJean, Arnaud; Gagnadoux, Marie-France; Daudon, Michel; Jungers, P. (1999). "Treatment of cystinuria". Pediatric Nephrology. 13 (9): 945–50. doi:10.1007/s004670050736. PMID   10603157. S2CID   20984151.
  10. ↑ Zee, Tiffany; Bose, Neelanjan; Zee, Jarcy; Beck, Jennifer N.; Yang, See; Parihar, Jaspreet; Yang, Min; Damodar, Sruthi; Hall, David (March 2017). "α-Lipoic acid treatment prevents cystine urolithiasis in a mouse model of cystinuria". Nature Medicine. 23 (3): 288–290. doi:10.1038/nm.4280. ISSN   1078-8956. PMC   5656064 . PMID   28165480.
  11. 1 2 "Alpha-lipoic acid prevents kidney stones in mouse model of rare genetic disease: Research leads to clinical trial for cystinuria". ScienceDaily. Retrieved 2017-07-09.
  12. ↑ D Bannasch; PS Henthorn (2009). "Changing Paradigms in Diagnosis of Inherited Defects Associated with Uroliths". Veterinary Clinics of North America: Small Animal Practice. 39 (1): 111–125. doi:10.1016/j.cvsm.2008.09.006. PMC   2628803 . PMID   19038654.
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