Children who are presented for genetic screening in order to evaluate whether they inherited mutated genes from their parents are generally asymptomatic.

In most cases, cystinuria is diagnosed in adolescents or young adults who present with symptoms of urolithiasis, i.e., who report hematuria, recurrent infections of the urinary tract and chronic pain in lower back and abdomen. Some patients may seek out emergency services because of a renal colic and acute, intense pain. Fever, night chills, nausea and vomiting may be observed in severe cases.

In general, obstruction of the urinary tract by cystine calculi does not cause any symptoms that allow for clinical distinction between cystinuria and other diseases associated with urolithiasis. Although the excretion of urine smelling for rotten eggs may imply high sulphur content, this finding is neither specific nor observed in every patient. In contrast, a familial history of urolithiasis may be highly indicative of cystinuria.

• Asymptomatic

  Children who are presented for genetic screening in order to evaluate whether they inherited mutated genes from their parents are generally asymptomatic. [symptoma.com]

  Stone free rates were 46% for group A and 50% for group B patients but all group B patients were asymptomatic at the time of our review. [ncbi.nlm.nih.gov]

  Type A heterozygotes are generally asymptomatic while type B heterozygotes usually have a three-fold increased incidence of kidney stones compared to the general population. [moh-it.pure.elsevier.com]

  Asymptomatic Stone Formers With the increased use of computed tomography (CT) and other radiographic imaging, incidental asymptomatic kidney stones often are detected without pain or gross hematuria being present. [doi.org]

• Severe Pain

  Renal Colic (severe pain in the back, side and groin area) is often the first sign. Information about the service Patients with Cystinuria will be seen in the specialist renal metabolic clinic. [uhb.nhs.uk]

  Although cystinuria itself doesn’t cause noticeable symptoms, the increased concentration of cystine puts patients at risk of kidney stone formation, which can lead to severe pain and other related complications. [news-medical.net]

  Renal colic is described as a moderate to severe sharp spasmodic pain in the back, side and groin area, often traveling from front to back. Over time it can be tracked downwards. Sometimes it is described as the worst pain a patient has ever had. [web.archive.org]

  The symptoms may include: blood in the urine severe pain in the side or the back, almost always on one side nausea and vomiting pain near the groin, pelvis, or abdomen Cystinuria is asymptomatic, meaning it causes no symptoms, when there are no stones [healthline.com]

• Inflammation

  To our knowledge, this is the first successful proteomic study in cystinuria unmasking the potential role of inflammation in this disease. [ncbi.nlm.nih.gov]

  Description: Accumulation of cystine in kidney, which may further precipitate to form calculi (stones) and inflammation of the system Symptomes: Difficulties to urinate, there may be blood in urine. [antagene.com]

  Cats suffering from Cystinuria suffer repeated urinary tract inflammations, and are at risk for urinary blockage, which can, if not treated promptly, lead to kidney failure, bladder rupture, and death. [shop.labogen.com]

  Chronic pyelonephritis from an infected struvite stone will lead to inflammation and eventual destruction of renal parenchyma ( 40 ). [doi.org]

• Chills

  Fever, night chills, nausea and vomiting may be observed in severe cases. [symptoma.com]

  Photo Credit Dolly Faibyshev for The New York Times Work Out and Chill? Cool temperature workouts may be the answer for those who want to exercise without becoming a hot mess. [nytimes.com]

  Call your doctor immediately if you have any signs or symptoms such as fever, sore throat, chills, bleeding, or if you are bruising more easily. [thiola.com]

  Impairment in taste or smell Dermatologic (pharyngitis, oral ulcers, rash, ecchymosis, pruritus, urticaria, warts, skin wrinkling, pemphigus, elastosis perforans serpiginosa) Hypersensitivity reactions (laryngeal edema, dyspnea, respiratory distress, fever, chills [thiolahcp.com]

• Abdominal Pain

  Advicenne’s multi-particulate formulation provides prolonged release and absorption of potassium citrate and potassium bicarbonate along the gastrointestinal tract while avoiding abdominal pain. [advicenne.com]

  These may include: Blood in urine Severe pain in the back (usually unilateral, on one side) Nausea Vomiting Abdominal pain Homozygous cystinuria involves chronic, recurrent kidney stones and can be difficult to manage effectively. [news-medical.net]

  pain, bloating, flatus) Impairment in taste or smell Dermatologic (pharyngitis, oral ulcers, rash, ecchymosis, pruritus, urticaria, warts, skin wrinkling, pemphigus, elastosis perforans serpiginosa) Hypersensitivity reactions (laryngeal edema, dyspnea [thiolahcp.com]

  Additional side effects that have been reported during treatment with d-penicillamine and that might occur during THIOLA treatment include: decreased sense of smell, nausea, vomiting, diarrhea or soft stools, loss of appetite, abdominal pain, bloating [thiola.com]

• Diarrhea

  Such effects include nausea, diarrhea, altered taste perception, fever, nephrotic syndrome, dermatitis, arthropathy, myalgia, muco-cutaneous lesions, pancytopenia, and zinc and copper deficiencies [8]. [tandfonline.com]

  […] friability of skin Jaundice and abnormal liver function tests (in non-cystinuric conditions) THIOLA is associated with fewer or less severe reactions than d-penicillamine, however the following adverse reactions may occur: Gastrointestinal (nausea, emesis, diarrhea [thiolahcp.com]

  Additional side effects that have been reported during treatment with d-penicillamine and that might occur during THIOLA treatment include: decreased sense of smell, nausea, vomiting, diarrhea or soft stools, loss of appetite, abdominal pain, bloating [thiola.com]

• Jaundice

  […] during the first month Generalized rash with pruritus Lupus erythematous-like drug reaction (e.g., fever, arthralgia, lymphadenopathy, positive antinuclear antibody test) Hypogeusia Vitamin B 6 deficiency (uncommon) Wrinkling and friability of skin Jaundice [thiolahcp.com]

  Jaundice (yellow appearance of the skin and whites of the eyes) and abnormal liver function tests have been reported during THIOLA treatment for conditions unrelated to cystine stones. Call your doctor for medical advice about side effects. [thiola.com]

• Blister

  Seek immediate medical attention and discontinue THIOLA if you notice symptoms such as fever, sore throat, chills, bleeding, easy bruising, coughing up blood, muscle weakness, blistering or raw areas on the skin or mucous membranes, joint pain, swelling [thiola.com]

• Back Pain

  CASE REPORT An 8 years old girl was referred to our hospital for recent UTI and low back pain on both sides. Renal ultrasound showed kidney stones on both sides and a grade II of hydronephrosis on the right. [adc.bmj.com]

  Symptoms may include acute episodes of abdominal or lower back pain, presence of blood in the urine (hematuria), and recurrent episodes of kidney stones may result in frequent urinary tract infections, which may ultimately result in renal insufficiency [mayomedicallaboratories.com]

  Symptoms of kidney stones as a result of cystinuria may include: Hematuria Unilateral back pain Nausea and vomiting In addition, some individuals may be affected by psychological symptoms as a secondary effect of the condition. [news-medical.net]

• Low Back Pain

  CASE REPORT An 8 years old girl was referred to our hospital for recent UTI and low back pain on both sides. Renal ultrasound showed kidney stones on both sides and a grade II of hydronephrosis on the right. [adc.bmj.com]

• Hyperactivity

  A 7-year-old boy with speech delay, hyperactive behavior, and minor neurologic abnormalities had been found in the past to have "intermittent cystinuria." [ncbi.nlm.nih.gov]

• Nephrolithiasis

  However, the excessive urinary cystine excretion leads to cystine nephrolithiasis. Clinically, cystine stones manifest in the same way as other forms of nephrolithiasis with hematuria and colicky flank pain radiating to the groin. [visualdx.com]

  Cystinuria is an autosomal recessive hereditary disorder associated with nephrolithiasis and its attendant complications. [ncbi.nlm.nih.gov]

  Finally, this patient has yet to experience a single symptomatic nephrolithiasis, which is remarkable, considering the cumulative risk for nephrolithiasis in patients with PKD in general and this patient in particular. [academic.oup.com]

  Halbritter J, Baum M, Hynes AM, Rice SJ, Thwaites DT et al. (2014) Fourteen monogenic genes account for 15% of nephrolithiasis / nephrocalcinosis. [omicsonline.org]

• Hematuria

  Testicular tumors Ovarian torsion or rupture Biliary colic and cholecystitis – Hematuria is not a feature of these diseases. Mesenteric ischemia – Hematuria is not a feature of this disease. [visualdx.com]

  Cystine stones present similarly to other renal stones: flank pain, nausea and vomiting, hematuria. [radiopaedia.org]

  Symptoms may include acute episodes of abdominal or lower back pain, presence of blood in the urine (hematuria), and recurrent episodes of kidney stones may result in frequent urinary tract infections, which may ultimately result in renal insufficiency [mayomedicallaboratories.com]

  Signs and symptoms of the condition are related to the presence of stones and may include nausea, hematuria, flank pain, and/or frequent urinary tract infections. [rarediseases.info.nih.gov]

• Flank Pain

  Cystine stones present similarly to other renal stones: flank pain, nausea and vomiting, hematuria. [radiopaedia.org]

  Clinically, cystine stones manifest in the same way as other forms of nephrolithiasis with hematuria and colicky flank pain radiating to the groin. [visualdx.com]

  Case Scenario 12-year-old girl presented to pediatrician with chief complaints of sudden sever right flank pain associated with nausea and vomiting. On physical examination tenderness in the right upper quadrant and flank is noticed. [creativemeddoses.com]

  The stone are responsible for all the signs and symptoms of cystinuria, including: Hematuria -- blood in the urine; Flank pain -- pain in the side, due to kidney pain; Renal colic - intense, cramping pain due to stones in the urinary tract; Obstructive [rxlist.com]

• Renal Injury

  They were diagnosed with acute post-renal injury due to obstructive bilateral ureteral stones based on ultrasound scan findings. Immediately, bilateral ureteral stents were inserted for urinary drainage. [ncbi.nlm.nih.gov]

  The presence of hydroxyapatite crystals in either the interstitial or tubule compartment (and sometimes both) of the renal medulla in stone formers is the rule and has implications for the initial steps of stone formation and the potential for renal injury [scienceopen.com]

  Extracorporeal SWL is widely used to treat renal stones 29 ). SWL has been shown in animal models to induce parenchymal injury that increases with the number of shocks, with level of energy, and with smaller kidneys. [doi.org]

Primarily, the presence of calculi within the urinary tract needs to be confirmed. In order to do so, standard procedures like plain radiography and urography are applied. In cystinuria patients, calculi, particularly Staghorn calculi, are generally detected in both kidneys.

Secondly, the cause of (recurrent) urolithiasis needs to be evaluated in order to decide on an adequate therapeutic approach. Here, microscopic urine analysis is the method of choice to confirm an increased excretion of cystine. It yields positive results in the vast majority of patients and monomorphic, hexagonal crystals that are often compared to benzene rings are readily visible in their urine samples. However, food and fluid intake may alter the results of urine analysis and the absence of cystine crystals does not rule out the disease. Also, hypercalciuria, hyperuricosuria and hypocitraturia are frequent additional findings in cystinuria patients [9]. In order to make urine analysis results more reliable, various additional tests can be performed: They aim at assessing cystine concentrations either by titration and observation of color changes or by induction of cystine precipitation [10] [11]. If such tests suggest cystinuria, cystine excretion over 24 hours should be evaluated. While healthy individuals don't excrete more than 80 mg per day, more than 200 mg per day are diagnostic of cystinuria.

If anamnestic data and the patient's familial history support the tentative diagnosis of cystinuria, genetic screens are recommended to confirm the diagnosis and to identify the precise mutation causing cystinuria in an individual patient. This information also allows for drawing of conclusions regarding inheritance patterns and the risk of a patient's future children to develop the disease.

• Nephrolithiasis

  However, the excessive urinary cystine excretion leads to cystine nephrolithiasis. Clinically, cystine stones manifest in the same way as other forms of nephrolithiasis with hematuria and colicky flank pain radiating to the groin. [visualdx.com]

  Cystinuria is an autosomal recessive hereditary disorder associated with nephrolithiasis and its attendant complications. [ncbi.nlm.nih.gov]

  Finally, this patient has yet to experience a single symptomatic nephrolithiasis, which is remarkable, considering the cumulative risk for nephrolithiasis in patients with PKD in general and this patient in particular. [academic.oup.com]

  Halbritter J, Baum M, Hynes AM, Rice SJ, Thwaites DT et al. (2014) Fourteen monogenic genes account for 15% of nephrolithiasis / nephrocalcinosis. [omicsonline.org]

• Hypouricemia

  Normal urate transport into erythrocytes in familial renal hypouricemia and in the Dalmatian dog. Can Med Assoc J. 1983; 128 :545. [ PMC free article ] [ PubMed ] [ Google Scholar ] 54. Wallerstrom BI, Wagberg TI. [ncbi.nlm.nih.gov]

Although general measures like physical destruction (by means of percutaneous nephrolithotripsy) or surgical removal of calculi may be applied as a kind of symptomatic therapy, both dietary adjustments and medication are required to avoid recurrent urolithiasis. The majority of cystinuria patients suffers from relapses within a few months if the underlying disease is not identified and adequately treated.

In detail, the following is recommended:

• Restriction of salt and protein consumption to reduce the amounts of cystine that are filtered in the first place.
• High fluid intake. Increased amounts of urine reduce cystine concentrations and thus decrease the likelihood of precipitation. Additionally, previously existing, small cystine calculi may be dissolved by means of high fluid intake. Cystinuria patients are recommended to drink four liters throughout the day.
• Alkalization of urine. At increased pH values, solubility of cystine is higher. Consequences are similar to those described for high fluid intake. However, the risk of formation of other types of calculi should be considered.
• Administration of penicillamine or tiopronin. These drugs combine with cystine to form highly soluble compounds.

Of note, the above described techniques to assess urinary cystine concentrations are very helpful to evaluate a patient's response to therapy. Experience shows that therapeutic success can be observed most easily in morning urine samples.

Life-long medication and adherence to recommendations regarding dietary adjustments are required - if patients are willing to comply, the risk of recurrent urolithiasis can be diminished to approximately 25%. Cystinuria patients have a normal life expectancy if permanent renal damage is avoided by means of dietary adjustments, medication and timely initiation of treatment in episodes of urolithiasis.

Mutations of genes SLC3A1 / rBAT (to be encountered at position 2p16.3) and SLC7A9 / BAT1 (located at position 19q13.1) have been associated with cystinuria. Accordingly, the following types of cystinuria have been defined:

• Type I cystinuria / type A cystinuria patients are homozygous for SLC3A1 mutations. This type of the disease is inherited with an autosomal recessive trait, i.e., in order for a patient to develop the disease, they need to inherit defective alleles from both parents. Individuals who are heterozygous for the causative allele will not suffer from cystinuria; they are, however, carriers and play an important role in disease epidemiology. People suffering from type I cystinuria don't show alterations in amino acid urinary patterns, which is why the condition may also be referred to as silent cystinuria.
• Non-type I cystinuria, which has previously been subdivided into type II and type III cystinuria. This subclassification is based on the presence of amino acid transport alterations in the gastrointestinal tract, a pathologic condition that may be observed in type II cystinuria but that is not present in type III patients. SLC7A9 mutations, presumably inherited with an autosomal dominant trait and showing incomplete penetrance, have traditionally been assumed to cause non-type I cystinuria. However, newer proposals regarding cystinuria classification consider people that present with two SCL7A9 mutations as type B cystinuria patients and describe a third AB cystinuria variant caused by one mutation of SLC3A1 and one mutation of SLC7A9 [2]. Unfortunately, it is also not sure if this classification holds true since other researchers claim to have identified SLC7A9 mutations in all types of cystinuria [3].

Thus, there is considerable confusion regarding distinct forms of the disease. While the classical type I, II, III system is based on clinical parameters, the genetic background may be more complex than currently assumed [4]. Variants of genes not yet related to cystinuria may affect penetrance and expressivity of SLC3A1 and SLC7A9. The observation that some cystinuria patients are heterozygous for mutations in both of these genes supports the hypothesis of gene-gene interaction.

The worldwide prevalence of cystinuria has been estimated to be about 1 per 7,000 people. However, local prevalence varies largely and may be as low as 1 per 100,000 inhabitants in Northern Europe or as high as 1 per 2,500 among Libyan Jews [5]. Also, certain mutations are frequently observed in some ethnicities and very rarely occur in others. The aforementioned population of Libyan Jews, for instance, commonly suffers from non-type I cystinuria due to an SLC7A9 V170M mutation [6]. In contrast, Italian and Spanish cystinuria patients most frequently show an SLC3A1 variant with an M467T mutation [7]. To date, is not clear whether cystinuria patients necessarily develop urolithiasis. If that's not the case, the disease may never be diagnosed and consequently, prevalence rates would be underestimated.

According to available epidemiological data, men are at higher risks of cystinuria-related urolithiasis than women although the genetic disorder affects both genders equally.

If urine samples of affected children are analyzed, cystinuria may be detected. About one out of four cystinuria patients presents with calculi during their first decade of life. Otherwise, urolithiasis becomes an issue during adolescence or early adulthood and prompts patients to seek medical attention.

Primary urine is essentially an ultrafiltrate of blood, i.e., it contains distinct amino acids in concentrations similar to those measured in serum samples. In order to limit amino acid loss, the vast majority of these compounds is reabsorbed. In healthy individuals, less than 1% of filtered cystine amounts are finally excreted. Both a high-affinity/low-capacity and a low-affinity/high-capacity system are responsible for the recovery of cystine, lysine, arginine and ornithine, whereby cystine reabsorption is primarily carried out by the former. This high-affinity system is disturbed in cystinuria patients. Even though reabsorption of lysine, arginine and ornithine is also impaired, it is the low solubility of cystine that triggers formation of calculi and thus accounts for cystinuria-associated morbidity [8].

Affected families may benefit from genetic counseling.

Individuals suffering from cystinuria should strictly adhere to recommendations regarding diet and drug therapy to avoid recurrent urolithiasis.

In the broader sense of the word, cystinuria is the medical designation for urinary excretion of the amino acid cystine. In practice, the term is rather used for the genetic disorder that causes the aforementioned condition. In this context, cystinuria is a disease caused by mutations of distinct genes located on chromosomes 2 and/or 19 [1]; it is generally inherited with a recessive trait, but dominant patterns of gene expression have also been described. The respective genes encode for amino acid transporters whose substrates are cystine, lysine, arginine and ornithine. They are expressed in kidneys and intestines. Consequently, cystinuria patients may show alterations in renal and intestinal amino acid metabolism. Cystine's low solubility in urine is what causes symptoms of cystinuria.

Detection of characteristic crystals during urine analyses is considered pathognomonic for cystinuria and indicates that the urinary concentration of this amino acid is exceeding its solubility. Therefore, patients suffering from cystinuria present with recurrent urolithiasis and associated pathologies, e.g., renal colic, hydronephrosis and recurrent infections of the urinary tract. As long as there are no calculi in the urinary tract, cystinuria patients are asymptomatic. Thus, in general, the aforementioned diseases lead to urinary analysis and identification of cystinuria as the primary cause of complaints. Genetic screens may confirm the diagnosis of cystinuria.

Cystinuria is the medical term for urinary excretion of the amino acid cystine. This condition is associated with a significantly increased risk of urolithiasis and is caused by distinct genetic disorders.

Causes

Both kidneys form primary urine by ultrafiltration of blood, i.e., primary urine contains many different ingredients that the human body can't afford to lose. Therefore, primary urine is passed through a long system of tubules and most of these compounds as well as water are reabsorbed. In patients suffering from cystinuria, tubular reabsorption of the amino acid cystine is disturbed. Mutations of genes encoding for amino acid transporters expressed in epithelial cells lining those tubules account for the disease. While cystinuria does not cause cystine deficiency, the low solubility of cystine in urine causes this amino acid to precipitate and to form calculi.

Symptoms

Because cystinuria is a genetic disorder, functional impairment of renal amino acid transporters may cause formation of calculi very early in life. Most cystinuria patients present in adolescence or early adulthood with symptoms of urolithiasis, but this complication of the disease may already occur in childhood. Urolithiasis, i.e., the presence of calculi in the urinary tract, may cause renal colic, hydronephrosis or recurrent infections of the urinary tract. Very common symptoms are the presence of blood in urine and intense pain.

As long as no calculi obstruct the urinary tract, cystinuria patients are asymptomatic.

Diagnosis

Urolithiasis is diagnosed by means of physical examination and diagnostic imaging. However, neither of these techniques allows for the identification of the underlying disease. In order to confirm cystinuria, urine samples have to be analyzed for increased concentrations of this amino acid. This test yields positive results that are considered pathognomonic for cystinuria. Subsequently, genetic screens are realized to determine the precise gene mutation.

Treatment

Both dietary adjustments and medication are required to avoid recurrent urolithiasis due to cystinuria. In detail, the following measures are indicated:

• Restriction of salt and protein consumption to reduce the amounts of cystine that are filtered in the first place.
• High fluid intake to reduce urinary cystine concentrations, diminish the likelihood of formation of new calculi and possibly even dissolve previously existing stones. Cystinuria patients are recommended to drink four liters throughout the day.
• Increase of urinary pH values. At increased pH values, solubility of cystine is higher. Consequences are similar to those described for high fluid intake.
• Administration of penicillamine or tiopronin. These drugs combine with cystine to form highly soluble compounds.

1. Saravakos P, Kokkinou V, Giannatos E. Cystinuria: current diagnosis and management. Urology. 2014; 83(4):693-699.
2. Dello Strologo L, Pras E, Pontesilli C, et al. Comparison between SLC3A1 and SLC7A9 cystinuria patients and carriers: a need for a new classification. J Am Soc Nephrol. 2002; 13(10):2547-2553.
3. Leclerc D, Boutros M, Suh D, et al. SLC7A9 mutations in all three cystinuria subtypes. Kidney Int. 2002; 62(5):1550-1559.
4. Harnevik L, Fjellstedt E, Molbaek A, Denneberg T, Soderkvist P. Mutation analysis of SLC7A9 in cystinuria patients in Sweden. Genet Test. 2003; 7(1):13-20.
5. Weinberger A, Sperling O, Rabinovitz M, Brosh S, Adam A, De Vries A. High frequency of cystinuria among Jews of Libyan origin. Hum Hered. 1974; 24(5-6):568-572.
6. Sidi R, Levy-Nissenbaum E, Kreiss Y, Pras E. Clinical manifestations in Israeli cystinuria patients and molecular assessment of carrier rates in Libyan Jewish controls. Isr Med Assoc J. 2003; 5(6):439-442.
7. Gasparini P, Calonge MJ, Bisceglia L, et al. Molecular genetics of cystinuria: identification of four new mutations and seven polymorphisms, and evidence for genetic heterogeneity. Am J Hum Genet. 1995; 57(4):781-788.
8. Fjellstedt E, Harnevik L, Jeppsson JO, Tiselius HG, Soderkvist P, Denneberg T. Urinary excretion of total cystine and the dibasic amino acids arginine, lysine and ornithine in relation to genetic findings in patients with cystinuria treated with sulfhydryl compounds. Urol Res. 2003; 31(6):417-425.
9. Sakhaee K, Poindexter JR, Pak CY. The spectrum of metabolic abnormalities in patients with cystine nephrolithiasis. J Urol. 1989; 141(4):819-821.
10. Nakagawa Y, Coe FL. A modified cyanide-nitroprusside method for quantifying urinary cystine concentration that corrects for creatinine interference. Clin Chim Acta. 1999; 289(1-2):57-68.
11. Goldfarb DS, Coe FL, Asplin JR. Urinary cystine excretion and capacity in patients with cystinuria. Kidney Int. 2006; 69(6):1041-1047.