2
The Frustration of Living with an “Orphan Disease”:
Contradictions, Misconceptions, and Lack of Studies
Cystinuria Versus Common Kidney Stones
Cystinuria is often mistaken by the medical community for a simple case of a kidney stone or stones. Cystine stones are anything but common and are specifically caused by a rare metabolic disorder that is present at birth. Cystinuria is a rare birth defect (inherited disorder) that causes an abnormal transport in the renal and gastrointestinal system of 4 amino acids (cystine, ornithine, lysine, and arginine). Cystine is not soluble in normal urine and is extremely difficult to treat. It must be monitored frequently according to patient history of formation and requires life-long therapy. Cystine (a protein building block) stones are formed by the abnormal excretions of the amino acid, cystine. Depending upon the severity of the case, the majority of sufferers have cystine crystals and stones present at each urination. These patients live in chronic pain from excessive surgeries (including damage from and limited to), UTI infections, crystalluria (cystine crystals), and cystine stones that plague their entire urinary tract system with pain that consumes their everyday lives. In addition, these patients suffer from fatigue, nausea, fever, and depression among others symptoms. Where as the common stone (calcium, struvite, or uric acid) former may know exactly how many stones are formed by the number of emergency room visits and Xrays, a Cystinuric will pass abnormal amounts of cystine at each urination and has a continual excretion of cystine stones or crystals exiting or forming in the renal or urinary tract at any given time. A ER visit for a Cystinuric is just an indication that a particular cystine stone or stones took longer than 2-3 days to pass or the patient may feel indications of hydronephrolis (urinary blockaged) usually accompanied with a funny taste in the mouth for a prolonged period of time. This does not mean that a Cystinuric will not pass large stones at home. On the contrary, a Cystinuric has to constantly access the need for critical care by their pain level. Most Cystinurics, because the condition is present at birth, will develop an unusually high pain tolerance and can overtime pass much more larger stones without medical intervention as oppose to other stone formers. It does not, however, mean that Cystinurics do not suffer. For many Cystinurics, social, financial, work, and household obligations cannot be performed because of chronic pain both pelvic and flank, low grade fever, fatigue, insomnia, crystalluria, cystine stones, infections and other related symptoms. Not to mention, the multiple acute situations that will arise with this difficult to treat illness.
Unlike other more common (calcium, struvite, and uric acid) kidney stones where there is an accumulations over a time frame or period of time (a year to six months in the most extreme cases for common stones), a Cystinuric's kidneys is a relentless cystine depository. There is no current drug to cure or prevent these abnormal, massive excretions because of the defective renal transporter. Because stones can literally form overnight, patients must keep a 24 hour vigil to flush out these cystine crystals and stones. Typically, cystine does not respond to treatments such a traditional lipotripsy or whirlpool shockwave. As a result, much more advance and expensive equipment is needed. Ironically, the best and only conclusive treatment for Cystinuria is to excessively hydrate in order to flush cystine crystals and pass stones as often as possible to avoid staghorns. It is no wonder that Cystinurics suffer from fatigue, insomnia, constant pain, and depression.
The amount of cystine a Cystinuric will excrete is determine upon how badly the defect of transport system is at birth. Commonly, the earlier a person develops symptoms (not actually diagnosed) of Cystinuria, the more damaged their transport system may be. This could contribute to the spectrum of severity and contribute to the conflicting studies on drug effectiveness and other such contradictory reports on drug and treatments.
A person may start to show symptoms at any decade of life. However, the earlier the decade of symptom rate, the assumption is the more severe degree of impairment of the transport system. Infants and young children may not be diagnosed properly due to cystine crystalluria not being visible on Xrays or Ct scans. Pure cystine stones are either not visible or difficult to see in a X-ray (KUB). The composition of rare cystine as oppose to other common stones (calcium, struvite, or uric acid) may be the culprit of why cystine crystalluria (crystals in the urine) is so painful.
There are conflicting reports by professional regarding cystine stone formations. One might read that cystine stones represent less 1% than all kidney stones. There seems to be a misconception that cystine stones account for as much as 3% or less. This fluctuation my be attributed to the excessive rate of cystine tone formation as opposed to the actual number of cystine stone formers. Thus, Cystinurics have an extremely high rate of stone production without medical intervention to derail statistics.
According to Keck Graduate of Institute of Life Sciences,"Cystinuria is a serious orphan disease characterized by the accumulation of large amounts of cystine in urine. It is caused by a defect in the transporter assembly in renal proximal tubules that is responsible for the reabsorbtion of cystine and several other amino acids. Cystine accumulates in the urine in abnormally large amounts and, because of its insolubility, crystallizes to produce stones.
No rapid measurement of the concentration of cystine in urine currently exists. All current tests are time-consuming and require the submission of samples to laboratories. The KGI team working with BioCatalytics has developed a test strip for urinary cystine. This rapid, non-invasive test provides a means for early diagnosis of cystinuria and regular monitoring of urinary cystine concentrations which is expected to limit progression of the disease. The team has contributed to all aspects of the project, including assay optimization, manufacturing, market research and regulatory affairs." [18]
Conclusion: Although cystinurics account for less than 1% of all stone cases, the production rate of cystine stones as oppose to other stone formers (calcium, struvite, and uric acid) is altered because there is no way to determine the occurrence of stone formation of cystinurics due the accelerated rate of production and passage. Many cystinurics are unable to determine the number of stones because of this excessive rate. The variation may be due to the frequency of the cystine stone production in these rare carriers of cystinuria .
Rare diseases are usually chronic and life-threatening. This is so because, given its rarity, less severe illness are just not identified as such. Eurordis estimates that at least 80% of them have identified genetic origins. Other rare diseases are the result of infections and allergies or due to degenerative and proliferative causes. Symptoms of some rare diseases may appear at birth or in childhood, whereas others only appear once adulthood is reached.
Review the history to identify patients at high risk of recurrent stone disease . These include patients with underlying medical disorders that can cause nephrolithiasis, such as gout, RTA, hyperoxaluria, UTI, hyperparathyroidism, cystinuria, and hyperuricosuric hypercalciuria. These patients need medical therapy to prevent recurrence as well as to treat the underlying medical disorder.[10]
"Cystine Stones. About 2% of stones in adults and up to 8% of kidney stones in children are caused by a build-up of the amino acid cystine, a building block of protein. The tendency to form these stones is inherited. They are marked by rapid growth and recurrence, which, if not treated promptly, can eventually lead to kidney failure.
Causes of Cystine Stones. Cystine stones develop from genetic defects that cause abnormal transport of amino acids in the kidney and gastrointestinal system leading to a build-up of cystine, one of these amino acids. Researchers have identified two genes responsible for this condition: SLC3A1 and CLC7A9.
May respond poorly to most lithotripsy procedures and require open surgery. (Newer procedures may be helpful.)
The first-line treatment for cystine stones is increasing the alkalization of urine so the stone can dissolve . If alkalization fails, drugs such as d-penicillamine, alpha-mercaptopropionylglycine (tiopronine), or captopril may be used to lower cystine concentration. Fluid intake for cystine stones must be even more voluminous than for regular stones. The patient should uniformly drink at least four quarts of water over a 24-hour period. "[4]
Most procedures are more effective for calcium and uric acid stones and less effective for struvite and cystine stones, although new techniques may be improving their effects on all stones. [4]
Why are Cystinurics in so much pain?
The answer is obviously simple: Massive cystine excretions causing a multiple array of symptoms.
Consider this:
Many Cystinurics will be able to pass larger stones and unfathomably more frequent than a normal person noted in chart above because of intense frequency of cystine excretions occurs without medical intervention. Cystine crystalluria and passing stones are a part of life for most cystinurics and necessary to prevent further damage to the kidneys and to avoid “prolonged” obstruction. Accordingly, a Cystinuric will not be able to attend a clinic, hospital, or ER for each urination in the course of 24 hours everyday of their lives.
Though we all know drugs have side effects, the drugs offered in the treatment of Cystinuria and cystine crystalluria causes common and severe effects such as PROTEINURIA (Nephrotic Syndrom).
What is conclusive?
Long time therapy with any of the three most effective drugs (Captopril, Penicillamine and Thiola®) commonly causes Nephrotic Syndrome (Proteinuria) and usually cannot provide long term treatment. There is no current cure or treatment that reduces actual cystine excretions resulting from the birth defect in the renal or intestinal transport. Cystine crystals and stones respond more efficiently to a Cystinuric who has a lighter stone burden or has no existing staghorn to act as a catalyst for the massive cystine excretions to adhere. However, this also means that the Cystinuric will be passing more stones. A Cystinuric, because of the lifetime of excretions, may often be able to pass stones of well over 5mm without medical invention which is not meant to imply a lack of pain but rather the longevity of the disease and relentless passing of cystine. Most sufferers have become accustomed due to medical expenses and the knowledge that it is best to pass the stone, if possible, without surgical intervention. For this reason, Cystinurics are well stocked with pain medication. Cystine crystalluria and stones are a part of daily life for the Cystinuric with little understanding by the medical community due to it’s rarity and "orphan disease" status.
Please considering and read the following supportive literature:
B. L. Fariss; F. O. Kolb
Factors involved in crystal formation in cystinuria. Reduction of cystine crystalluria with chlordiazepoxide and during nephrotic syndrome
JAMA, Sep 1968; 205: 846 - 848.
PROS AND CONS--(ACE Inhibitor)
“Captopril A blood pressure medicine which is thought to be able to bind with cystine and make it more dissolvable. While safe and well tolerated, its effectiveness in cystine stone disease is unclear.”
http://www.kidneystonesbook.net/meds.html [2]
According to the Merck Manual, "Captopril is not as effective as pencillamine but is much less toxic."
There is a significant risk of developing Nephrotic Syndrome (proteinuria) while taking Captopril
JAMA : The Journal of American Medical Association
(Membership Required)
A. Weinberger; I. Oliver; J. Pinkhas; A. De Vries
Letter: Treatment of renal obstruction caused by cystine crystals or stones
JAMA, Aug 1974; 229: 1045.
J. Pinkhas A. De Vries ... [1]
ORIGINAL CONTRIBUTIONS:
Rachel M. Werner; Eric T. Bradlow
Relationship Between Medicare’s Hospital Compare Performance Measures and Mortality Rates
JAMA, December 13, 2006; 296: 2694 - 2702.
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S. G. Massry |
D. B. Case; S. A. Atlas; J. A. Mouradian; R. A. Fishman; R. L. Sherman; J. H. Laragh
Proteinuria during long-term captopril therapy
JAMA, Jul 1980; 244: 346 - 349.
M. J. Schreiber Jr; L. S. Fang
Renal failure associated with captopril
JAMA, Jul 1983; 250: 31. [1]
C. E. Grim
Diagnosis of unilateral renal artery lesions after captopril administration
JAMA, Jan 1985; 253: 346 - 347.
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R. H. Fletcher; S. W. Fletcher |
F. R. Meloni; J. J. Canary
Cystinuria with hyperuricemia
JAMA, Apr 1967; 200: 257 - 259.
Relevant Terms:
ACE Inhibitor A type of high blood pressure medicine which may decrease urinary citrate. ACE stands for Angiotension Converting Enzyme. This type of medication blocks the activity of an enzyme which would otherwise create chemicals in the body that would increase the blood pressure. [2]
Captopril: A blood pressure medicine which is thought to be able to bind with cystine and make it more dissolvable. While safe and well tolerated, its effectiveness in cystine stone disease is unclear. [3]
Potassium Citrate aka Polycitra K or Urocit K®
Pros and Cons--(Urine Alkalinizer)
This drug requires a strict vigil of the patient monitoring of urine pH levels. Ideally, a Cystinuric will monitor the urine for the optimum pH of (7.0-7.5 or higher). This drug cannot limit the cystine excretions produced by the defective renal transporter. However, in less severe patients, it may reduce the excretions formation of stone. Studies suggest that in some patients, the cystine once excreted becomes more soluble in this pH range. Although this may appear to be helpful due to the fact that cystine is the least soluble amino acid and very difficult to treat, there is no conclusive evidence that this drug helps cystine patients.
"Potassium citrate therapy is effective in increasing urinary pH and urinary citrate. However, high recurrence rate and persistent cystinuria in our patients emphasize the inadequacy of our treatment schedule in the prevention of recurrent cystine calculi.” [8]
For more severe patients or if cystine stone formations continues. At which time, the doctor usually prescribed captopril, an "orphan drug" or chelating agent (see below).
Polycitra K A liquid form of potassium citrate. Also available as crystals in a packet than can be mixed with water or juice.
http://www.kidneystonesbook.net/meds.html [2]
Urocit-K An oral tablet form of potassium citrate supplement. The wax matrix tablet will often appear in the stool and some patients don't realize that the medicine has been absorbed and only the empty wax shell is expelled.
http://www.kidneystonesbook.net/meds.html [2]
Fact: [Mission Pharmacal (the manufacturer of Urocit-K) does NOT list UROCIT-K (generic: potassium citrate) as a drug choice for cystine stones. However, the company does recommend. THIOLA®, tiopromin, for the prevention of cystine kidney stone formation] [11]
In addition, it does not list this drug (potassium citrate) as an effective treatment for Cystinuria or cystine stones in it’s package insert. http://www.urocit-k.com/
Conclusion: Urologist may recommend this drug as result of being effective with more common types of kidney stones as part of a routine practice with the more common calcium stones.
Sodium Bicarb
Baking Soda
This is no longer a recommended treatment for Cystinuria due to the high sodium content and the increase risk for hypertension. Of course, not all doctors are aware of this. However, reconsiderations may be recommended because of cost effectiveness over other treatments.
PROS AND CONS--
There is no misconception about penicillamine (Cuprimine®) and tiopronin (Thiola®) being the drugs of last resort due to the devastatingly common and unquestionable severe side effects.
(Last resort should be indicative that the above list may not work adequately or at all in some cystinuria patients)
“Cystine Stones
With cystine stones, urine output needs to be about 3 quarts per day. Potassium citrate is used to alkalinize the urine to pH 7-7.5. Patients are advised to decrease purines and sodium. If urinary cystine is very high, patients are placed on D-penicillamine or Thiola®.” [5] (see effectiveness of Potassium citrate above)
Tiopronin (Alpha MPG) (classified as an "orphan drug")
N-(2-Mercaptopropionyl) glycine
Alpha-Merchaptoprionyl glycine
Thiol drug
Thiola®
(Abstract)
The following is according to Mission Pharmaceutical (Prescribing Information):
INDICATIONS AND USAGE: Thiola® is indicated for the prevention of cystine (kidney) stone formation in patients with severe homozygous cystinuria with urinary cystine greater than 500 mg/day, who are resistant to treatment with conservative measures of high fluid intake, alkali and diet modification, and who have adverse reactions to d-penicillamine.
Cystine stones typically occur in approximately 10,000 persons in the
Since there are no known inhibitors of the crystallization of cystine, the stone formation is determined primarily by the urinary supersaturation of cystine. Thus, cystine stones could theoretically from whenever urinary cystine concentration exceeds the solubility limit. Cystine solubility in urine is pH-dependent, and ranges from 170-300 mg/liter at pH 5, 190-400 mg/liter at pH 7 and 250-500/liter at pH 7.5.
The goal of therapy is to reduce cystine concentration below it’s solubility limit. It may be accomplished by dietary means aimed at reducing cystine synthesis and by high fluid intake in order to increase urine volume and thereby lower concentration.
Unfortunately, the above conservative measures alone may be ineffective in controlling cystine stone formation in some homozygous patients with severe cystinuria (urinary cystine exceeding 500 mg/day)/ In such patients, d-penicillamine has been used as additional therapy. Like Thiola™, d-penicillamine undergoes thiol-disulfide exchange with cystine, thereby lowering the amount of sparingly soluble cystine in the urine.
However, d-penicillamine treatment is frequently accompanied by adverse reactions, such as dermatologic complication, hypersensitivity reactions, hematologic abnormalities, and renal disturbances. Thiola® may have a particular therapeutic role in such patients.
Contraindictions: The use of Thiola® during pregnancy is contraindicted, except in those with severe cystinuria where the anticipated benefit of inhibited stone formation clearly outweighs the possible hazards of treatment (see precautions)
WARNINGS: Despite apparent lower toxicity of Thiola™, Thiola®, may cause all the serious adverse reactions reported in d-penicillamine although no death has been reported to result directly from Thiola® treatment, a fatal outcome from Thiola® is possible, as has been reported with d-penicillamine therapy from such complications as aplastic anemia, agranulocystosis, thrombocytopenia, and Goodpasture’s syndrome or myasthenia gravis.
Proteinuria, sometimes sufficiently severe to cause nephritic syndrome, may develop from membranous glomerulopathy, A close observation of affected patients is mandatory.
The following complications, though rare, have been reported during d-pennicillamine therapy and could occur during Thiola® treatment. When there is abnormal urinary findings associated with hemoptysis and pulmonary infiltrates suggestive of Goodpasture’s syndrome, Thiola® treatment should be stopped. Appearance of the myasthenic syndrome or myasthenia gravis requires cessation of treatment. When Pemphigus-type reactions develop, Thiola® therapy should be stopped. Steroid treatment may be necessary.
http://www.missionpharmacal.com/docs/Thiola.pi.C04.00802.pdf
Thiola® (Alpha MPG) Used to help cystine dissolve more easily. Has fewer side effects than penicillamine. http://www.kidneystonesbook.net/meds.html [2] **Please see information on "orphan drugs" on page 1
Penicillamine (chelation therapy or chelate agent)
D-Penicillamine
Penicillamine D
Cuprimine®
Pyridoxine is generally prescribed concurrent with penicillamine to help avoid or counter neurological problems.
Although all drugs have some type of side effects, this drug is strictly used for patients who have have not responded to other drug therapys.
Merck abstract:
The following can found on Merck & Co., Inc.
Cuprimine®
(Penicillamine)
Physician planningto use penicillamine should thoroughly familiarize themselves with its toxicity. Special dosage considerations, and therapeutic benefits. Penicillamine should never be used casually. Each patient should remain constantly under the close supervision of the physician. Patients should be warned to report promptly any symptoms suggesting toxicity.
…Penicillamine is a chelating agent recommended for the removal of excess copper in patients Wilson’s disease.
…Penicillamine also reduces excess cystine excretions in cystinuria. This is done, at least in part, by disulfide interchange between penicillamine and crystine, resulting in the formation of penicillamine-cysteine disultife, a substance that is much more soluable than cystine and is excreted readily…
Indications:
CUPRIMINE is indicated in the treatment of Wilson’s disease, cystinuria, and in patients with severe, active rheumatoid arthritis who have to failed to respond to an adequate trial of conventional therapy…
…Cystinuria—Cystinuria is characterized by excessive urinary excretion of the dibasic amino acids, arginine, lysine, ornithine, and cystine, and the mixed disulfide of cysteine and homocysteine. The metabolic defect that leads to cystinuria is inherited as an autosomal, recessive trait. Metabolism of the affected amino acids is influenced by at least two abnormal factors: (1) defective gastrointestinal absorption and (2) renal tubular dysfunction.
Arginine, lysine, ornithine, and cysteine are soluable substances, readily excreted. There is no apparent pathology connected with their excretion in excessive quanities.
Cystine, however, is so slightly soluble at the usual range of urinary pH that it is not excreted readily, and so crystallizes and forms stones in the urinary tract. Stone formation is the only known pathology in cystinuria.
Normal daily output of cystine is 40 to 80 mg. In cystinuria, output is greatly increased and may exceed g/day. At 500 to 600 mg/day, stone formation is almost certain. When it is more than 300mg/day, treatment is indicated…
CONTRAINDICTIONS:
Except for the treatment of Wilson’s disease or certain patients with cystinuria, use of penicillamine during pregnancy is constraindicated. (see WARNINGS)…
WARNINGS:
The use of penicillamine has been associated with fatalites due to certain diseases such as aplastic anemia, agranulocytosis, thrombocytopenia, Goodpasture’s syndrome, and myasthenia gravis.
Because of the potential for serious hematological and renal adverse reactions to occur at any time, routine urinalysis, white and differential blood cell count, hemoglobin determination, and direct platelet count must be done twice weekly, together with monitoring of the patient’s skin, lymph nodes and body temperature, during the first month of therapy, every two weeks for the next five months, and monthly thereafter. Patients should be instructed to report promptly the development of signs and symptoms of granulocyopenia and/or thrombocytopenia such as fever, sore throat, chills, bruising or bleeding. The above laboratory studies should be promptly repeaded…
…Proteinuria and/or hematuria may develop during therapy and may be warning signs of membranous glomerulopathy which can progress to nephrotic syndrome. Close observation of these patients is essential…
…When penicillamine is used in cystinuria, an annual x-ray for renal stones is advised. [Large problematic] cystine stones form rapidly, sometimes within six months.
Up to one year or more may be required for any urinary abnormalities to disappear after penicillamine has been discontinued.
PRECAUTIONS:
ADVERSE REACTIONS:
Penicillamine is a drug with a high incidence of untoward reactions, some of which are potentially fatal.
Therefore, it is mandatory that patients receiving penicillamine therapy remain under close medical supervison throughout the period of drug adminsiration (See WARNINGS and PRECAUTIONS).
Please view the entire prescription information @ www.atonrx.com/prescribing_information/Cuprimine_PI.pdf
_____________________________________________________________________________________________________
“A retrospective study was conducted to assess the efficacy of D-penicillamine in the management of cystinuria, as well as to define the frequency and nature of untoward reactions to this drug. Fifty-six individuals were identified who, by stone analysis and/or biochemical studies, met the accepted diagnostic criteria for phenotypic cystinuria. The majority of these patients presented in the second decade of life with evidence of stone formation: renal colic, hematuria, and/or stone passage. Thirty-five individuals were considered to have clinically advanced cystinuria because they had required at least one urinary tract lithotomy. In these advanced cases, frequency of subsequent lithotomies and episodes of renal colic per 100 patient-years of observation were used as indices to measure the efficacy of D-penicillamine treatment. By both measurements, D-penicillamine significantly improved the clinical course of patients. The incidence of acute drug sensitivity reactions (rash, fever, and/or arthropathy) was in excess of 40 percent. Delayed drug-induced proteinuria occurred in 34 percent of treated patients. We conclude that D-penicillamine is useful in the treatment of cystinuria. Because of the significant number of untoward drug reactions, however, we believe the drug should be instituted only in selected, high-risk patients.
PMID: 7342491 [PubMed - indexed for MEDLINE]” [9]
Related Terms:
(Duplication is not an error and reflects conclusive results of two primary sources--please note: Work Cited to follow)
Pyridoxine Another name for Vitamin B-6. Steroids A group of medications with similar chemical compositions that resemble natural anti-inflammatory agents in the body. They have many side effects including fluid retention and increasing urinary calcium. Talwin A moderately strong pain medicine. Not an opioid.
http://www.kidneystonesbook.net/meds.html [2]
Pyridoxine: Another name for Vitamin B-6. Steroids A group of medications with similar chemical compositions that resemble natural anti-inflammatory agents in the body. They have many side effects including fluid retention and increasing urinary calcium. Talwin A moderately strong pain medicine. Not an opioid. [3]
Penicillamine A binding agent for cystinuria. Side effects are severe and common. Only about 50 percent of patients with cystinuria can tolerate this medication even though it is very effective.
http://www.kidneystonesbook.net/meds.html [2]
Penicillamine: A binding agent for cystinuria. Side effects are severe and common. Only about 50 percent of patients with cystinuria can tolerate this medication even though it is very effective. [3]
Bucillamine: Experimental drug that increases dissolvability of cystine. Expected to be more effective with fewer side effects than penicillamine. [3]
Current Clinical trials:
Cystone: Cystone for Treatment of Nephrolithiasis [19]
[1] JAMA : The Journal of American Medical Association
(Membership Required)
[2] The Kidney Stone Book, Chapter 24 “List of Medications”
http://www.kidneystonesbook.net/meds.html
[3] KidneyStone.org
http://www.urologystone.com/CH07TreatmentOptions/otherMedication.html
[4] Kidney Stone Health Basis
[5] Uro/Stone Center:
urostonecenter.com
910.362.8765
http://www.urostonecenter.com/prevention.asp
[6] Kidney Stones: 09/2001/ What are Kidney Stones?
http://www.reutershealth.com/wellconnected/doc81.html
[7] Kidney International: Official Journal of the International Society of Nephrology
http://www.nature.com/ki/journal/v59/n5/full/4492224a.html
[8] Journal of Urology. 2001 Jun;165 (6pt 2): 2328:30.
“Cystine Calculi in children: the results of a Metabolic Evaluation and Response to Medical Therapy”
[9] Yale J Biol Med. 1981 Nov-Dec:54 (6): 439-46
[10] Patient Education Resources: Modern Medicine: healthy patients/healthy practice
http://www.modernmedicine.com/modernmedicine/article/articleDetail.jsp?id=108310
[11] Mission Pharmacal ® © 2006 MISSION PHARMACAL COMPANY
http://www.missionpharmacal.com/about/randd.aspx
[12] Cystinuria: Renal Transport Abnormalities: Merck Manual Professional
www.merck.com/mmpe/sec19/ch291/ch291b.html
[13] Monteray Bay Urology Associates
[14] Urological Research, 1981:9(4):163-8. "Cystine Crystalluria and Urinary Saturation in Cystine and Non-Cystine Stones"
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7269003&dopt=Abstract
[15] Kidney International (2006) 69, 2227–2235. doi:10.1038/sj.ki.5000268; published online 17 May 2006
http://www.nature.com/ki/journal/v69/n12/abs/5000268a.html
[16] About: Kidney Stones "Cystine Kidney Stones" Your Guide to Kidney Diseases, Brian Lipp, MD
http://kidneydiseases.about.com/od/stonetypes/a/Overview0011.htm?terms=cystine+stones
[17] 15th October 2006 at 19:32 BST by Dr.C.A.Jenner MB BS, FRCA
http://www.londonpainconsultants.com/articles/2006/10/15/bladder_pain/
[18] Keck Graduate Institute of Applied Life Sciences
535 Watson Drive, Claremont, CA 91711 p (909) 607-7855 f (909) 607-8086
[19] Mayo Clinic: Clinical Trials (Experimental)
http://clinicaltrials.mayo.edu/clinicaltrialdetails.cfm?trial_id=100377
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