Cystinuric Perspectives (Living with Cystinuria and Chronic Cystine Stones)

INTRODUCTION: What is Cystinuria?

Cystinuria (cystine in the urine) is an inherited defect of the renal tubules where the amino acid, cystine, (a protein building block)  absorption is genetically impaired. Cystine and other amino acids are not fully metabolized by the kidneys and, in some cases, by the intestines as well. Cystinurics have difficulty fully metabolizing or reabsorbing four amino acids (cystine, lysine, ornithine, and arginine  acronym: COLA).  However, three of the four amino acids are easily soluble in urine causing no notable or chronic problems.  On the other hand, cystine is the least soluble of all amino acids therefore extremely difficult to treat. Cystinuria is a genetic birth defect or, more precisely, a congenital metabolic disease (an inborn error of metabolism). This disease has a broad spectrum--a few Cystinurics may produce no stones or few symptoms in a lifetime and never be diagnosed, but many may show stone formations or symptoms as early as infancy or childhood and have a lifetime of symptoms with chronic pain (frequently acute). Sufferers of this renal transport defect excrete abnormal amounts of cystine continually as evident in each urination.  For this reason, Cystinuria can be much more complicated to treat than with any other kidney stone former.  Because cystine excretions are continual, it is important to find a doctor who understands the complexity of this disease (constant monitoring by a reliable physician is mandatory) Stones may be formed and will be passed in a much more accelerated rate than other stone disease because of the metabolism of these amino acids being inhibited in the kidneys.  Because of the sheer volume of cystine excreted, sufferers generally must monitor their own pain and access their need for emergency care by a high fever and prolonged blockaged (over 2-3 days).  It would be highly impractical and inconceivably expensive for these individuals to seek care for each stone occurence since passage of cystine stones and crystals are endless.  It is not uncommon for a patient to pass multible medium-large painful stones in a day,but it often may take a week or longer. Cystine, an amino acid, is present in all types of food.  The avoidance of cystine consumption aka as a low-methionine diet is not a viable, lifetime option. It is important to avoid the consumption of animal proteins. 

Most treatments are ineffective or have inconclusive studies. The disease is also difficult to treat because of the composition of cystine crystals.  Despite recurrent symptoms, often children of earlier generations were not appropriately diagnosed until the second or third decade in their life.  A person with this disease may be diagnosed at any decade in life.  However, the earlier one shows symptoms, the more of an indicative of  how serious a person is affected by higher cystine excretion and concentration levels.  There is currently no cure or treatment that can eliminate cystine from being excreted.  Furthermore, there are little studies showing the renal toxicity of massive cystine or damage caused by these excretions by cystinurics during the course of a lifetime.

 

Diagnosis is confirmed by observing a cystine excretion of of > 400 mg/day.  This cystine level is specifically a result of an inborn renal tubule transport error and is considered abnormal.

Cystine stones and cystine crystalluria are caused exclusively by having this extremely rare renal transport disease (cystinuria) which is present at birth

Synonyms: (Renal) Cystine Transport Disease, Cystine Stone Disease, Cystiuria, Inborn Renal Aminoaciduria, Inborn Renal Tubular/Tubule Transport Error, Cystinuria-Lysinuria, Cystine-Lysine-Arginine-Ornithinuria, Aminoaciduria, Cystinuria with Dibasic Aminoaciduria, Cystine Calculi, and Inborn Aminoacid Metabolism Disorder.

 

Broad Term: Inborn Biological Transport Disorder, Inborn Error of Metabolism, Congenital Metabolic Disease,and Inherited Metabolic Disease.

Related Terms: Cystinosis, Hyperaminoaciduria, Oculocerbrorenal syndrome, Hartnup Disease, and Renal Tubule Acidosis

 

Cystine stones are prone to infection, particular with Proteus mirabilis.  Because of the massive cystine excretions (crystalluria), the patients are also in an increase risk of infection especially, Proteus mirabilis, among others and chronic pain associated with the lower back and pelvis.  After time, infection strands found in these individuals become highly mutated and difficult to treat.

 

Crystalluria In Cystinuria

Most commonly, crystalluria (crystals in the urine) is not only a symptom of Cystinuria, but also the menacing source of pain and cause of  further symptoms. Literally, a Cystinuric may form stones overnight. For this reason, a Cystinuric (person with the disease known as Cystinuria) must maintain a vigilant schedule of water intake and urinate throughout the day and night. Water is a considered a mandatory medication and lifeline for a Cystinuric.  An adult afflicted with this disease, should strive for at least a 4 liter output of a urine per day (in some cases more). This is double the output for a normal adult. This aids in  flushing out the ever present cystine crystals and stones.  Strangely,  the frequent the passage of cystine is the most desired outcome for a Cystinuric in order to avoid stones that need surgical intervention. This is because of the accelerated rate of stone growth. It is not uncommon for a Cystinuric to report visible cystine stones and crystals with pain on a daily basis.  The persistance promise of staghorns and relentless surgical removal  of cystine, not to mention the damage cystine causes in the kidney and urinary tract, may eventually cause scattered  parenchymal (tissue loss) or renal failure in some patients.  Thus, the Cystinuric is often either passing cystine stones or crystals at an accelerated pace or faced with having the cystine accumulate relatively quickly into staghorns or  into stones too large to pass through the ureter. This pain caused is unfathomable to most people outside of the sufferers. A cystinuric is able to pass much larger stones than a common stone former as well as an abundant of cystine crystals and stones without medical intervention since it is a daily part of the patient's life. In serious cases, chelation therapy may be needed. (These stones are the consistency of jagged crystals in texture and sharpness rather than a stone like appearance seen in other stones--see above and below)

Unlike other stone formers, Cystinurics may have chronic pain from the massive amount of cystine crystalluria present even when no visible obstruction is present on radiology test or hematuria (blood) present in the urine.  Chronic pain from cystalluria usually consist of pelvic and lower back pain. This pain is probably due to the massive presence of cystine crystalluria and the genetic structure of this aminoacid. Cystine is not very soluble. In fact, it is the least soluable of all amino acids.  Generally, it does not respond well to tradition lipotripsy or whirlpool shockwave due to its' genetic compostion and density. In short, cystine is generally either passed through the urinary tract or removed surgerical.   Also, pain may become acute at times even without presence of hematuria or despite an unremarkable CT scan. Cystine crystalluria is idiopathic by nature therefore no treatment is provided to these sufferers.  The human body was not made to pass stones and not able to cope with vast amount of crystals being passed by Cystinurics on a daily basis upon every urination at this accelerated rate.  Cystine crystalluria should not be equated with the normal stone formers passing of gravel either in size, frequency, or volume. Since this disease is so rare and extremely difficult to treat, its' current treatment is to pass the cytine before they accumulate in size and as often possible.   Although a Cystinuric has a much higher level of pain tolerance because of the frequency and longevity of pain endured throughout lifetime, it may be a contributing factor to why Cystinurics suffer such a high rate of depression. 

 

There is no treatment that can prevent cystine excretions or a cure at this time.

 

 

Understanding Cystinuria: The "Orphan Disease" that Care Forgot

   100% PURE CYSTINE surgically removed (13 y/o female)

 

Although many Cystinurics claim to respond considerably well to a low-methionine diet (A diet that consist of mainly fruit and a few vegetables. It allows very little, if any, meat, eggs, beans, seeds, seafood, dairy products, breads, or pastas).  There is no conclusive evidence that any success claim made by individuals that they are/were actually following a true low-methionine diet.  Outcomes may be tainted with severity of individual cases as well.  The information regarding this diet is controversial and contradictory.   Understandably, if someone is able to obtained correct information on this diet, it is extremely difficult to maintain and is not recommended for children or pregnant women.   Amino Acids are found in most living organism (plants or animals).  Thus, it is challenging to find foods low in these amino acids particularly ones low in methionine (precursor essential amino acid) which metabolizes into cystine.  Furthermore, it is very difficult to find dieticians who can supply information about this kind of diet because it is generally  not accepted as a healthy diet or one that is desired by the masses so information and studies are very limited 

Many prescribed drugs have ineffective results and conflicting studies of effectiveness (please refer to page 2). About 25% of all patients will continue to pass high levels of  cystine crystals and stones present in the urine at each urination, crystals (pictured on above).  Frequent cystine stone passage may or may not require an ER visit depending on the duration of acute pain (generally a patient will pass smaller to larger stones at home in 1-3 days (sometimes longer) provided the Cystinuric's temperature remains below 103°).  Also this group may be either unresponsive to treatment, maintain persistent low-grade fevers, or remain in chronic pain despite therapy.  Non responsive patients must resort to orphan drugs* like Tiopronin with Penicillimine, a drug therapy of last resort.  These drugs should be used as last resort treatment because of the common and severe side effects that can be fatal. Your doctors may order labwork twice a week for the first two weeks until gradually doing labwork monthly. The side effects can be as severe as the pain and side effects of cystine stones and crystalluria. These drugs are chelating agents and this type of drug therapy is known as chelation therapy. Chelating agents generally bond to toxic metals (in this case the amino acid, cystine--a protein building block) and helps to expell the toxin.  In the initial phase of therapy (1-3 months), patients may report an increase of stones ranging in size (30 or more) in each first morning urine collection alone. Chelating agents may cause nephrotoxicity (toxic or poisoning effects in the kidneys), neurological problems, and nephrotic syndrom aka proteinuria (protein in the urine).  Your doctor may prescribe vitamin B-6 (pyridoxine) in concurrent with this treatment to avoid a defiency that could cause neurological damage. According to the Merck Manual, only about 50% of patients can stay on this treatment for a significant period of time because of the severity of the symptoms. [12], (see page 2)  Your doctor may prescribed a sleeping pill to help "counteract" the intensive side effects of the drugs.   Regardless if someone is respondent or non respondent to treatment, it is important to note that there is presently no cure for Cystinuria nor is there any treatment that can actually eliminate or prevent cystine excretions. For severe sufferers, there is very little relief and some may eventual show evidence of parenchymal (dead tissue) in the kidneys and eventually renal failure. However, it is a slow, agonizing process. Understandably, Cystinurics often are depressed and experience bouts demoralization because of the symptoms associated with excessive cystine excretions and their inability to handle constant pain.  The Cystinuric often are unable to function or commit to social, work, or common household obligations. In addition, most Cystinurics will find it difficult to discuss their pain or have people understand their pain because it becomes evident that most people will never fathom how painful this disease can be.  Finally, the Cystinurics becomes conditioned to the pain as a part of normal life. Between the nightly vigil of hydration/urination, and relentless pain, understandably, Cystinurics will most likely suffer from chronic fatigue as well. 

Again, it is extremely important for the prolific cystine stone formers to dilligently seek out a nephrologist and urologist who does not view this as a case of common kidney stones.  Because cystine excretions are a direct result of an extremely rare metabolic disorder unlike other stones formation, it is an orphan disease**that is very complex to treat. (a disease with inconsistent information about treatment and considered to be rare disease--it orphaned by the medical community because of lack of cost effectiveness)  

Regardless of a patients response to therapy, there is a large spectrum in both stone formation, pain, and response to treatment.  Cystinurics on the severe end of the spectrum may experience renal failure.  Renal failure may be an outcome due to scar tissue (from both procedures and nephrotoxity), parenchymal (non functioning dead tissue), and of course, the damage resulting from the abnormal passing of massive quanities of  cystine in the form of crystals (crystalluria) and stones. The renal toxicity or damaging effects of excessive cystine levels throughout the span of a lifetime not fully understood at this time.  Because of the slow process of deteriation into renal failure, it is very a chronic, painful, and lifelong disease. More studies with a focus on concerns of and medical complaints from the disease carriers are needed. Most patients are self-educated through trial and error about the disease and are usually well versed in urological terminology because of their abnormal cystine stone occurence and frequent urological visits. 

Although renal stones are most often considered one of the most painful conditions known to man, the Cystinuric's life and pain tolerance is unfortunately unfathomable to almost everyone including some professionals in the medical field. In addition, in the few studies offered, the results present very contradictory views on this disease regarding treatment and the effectiveness of drugs (click link: Archives of Internal Medicine below).  As a result, is often difficult to find doctors in non-metropolitan areas who are knowlegable about the condition or has the complex medical equipment or experience to treat Cystinuria. A Physician, at least, should be aware of the accelerated of stone growth to avoid staghorns. A few staghorns in a lifetime will most like result in renal failure for a Cystinuric. Drug therapy works best when the kidneys are surgically cleared or free of large stone burdens or staghorns.  However, it is crucial to understand that once the stone burden is lighten, it may not help symptoms or pain and in all likelihood the patient will increase frequency of stone passage.  Because there is no treatment to prevent cystine excretions, the observations is that patient will pass more stones once the staghorn or staghorns are removed and no longer acts as a catalyst (a collection host).   Often, Cystinurics will feel distressed that passing more stones is the only solution to treat this disease. In normal stone formers who do not have this metabolic impairment, the treatment is considered successful once the staghorn or stone burden is removed.  With Cystinurics, once a Cystine staghorn is removed (if possible), it is only removing the catalyst for cystine accumillation--there is no treatment available to reduce cystine excretions or  to cure this metabolic impairment at this time short of replacing both kidneys. If one kidney is lost, the entire cystine excretion load will be concentrated onto one kidney.  Short of losing both kidneys, there is no cure.

Some Cystinurics show little symptoms and never or rarely have episodes of symptoms of stones.  Many Cystinurics learn quickly that passing stones is a better option than having them accumilate in the kidneys, bladders, or ureters. Again, hydration will help pass stones and crystals on a daily basis to flush out the kidneys and entire urinary tract.  Due to the hardness or composition of the cystine crystals, they are not always respondant to traditional types of lipotripsy.  Multiple open surgeries (not recommended for mild cases because of frequency--the preservation of kidney tissue is crucial) or percutaneous procedures, along with cystine stone passing and massive cystine crystalluria, may slowly result in parenchymal or eventually renal failure. Parenchymal or scar tissue eventually limits surgeries and percutaneous procedures as an option. For these patients, renal loss in inevitable.  This is why Cystinurics quickly discover that passing cystine crystals and stones is a better option than having them accumulate into staghorns the kidneys to prolong kidney function and avoid kidney loss. The treatment, both procedural and medicinal, can be as damaging to renal function and tissue as the abnormal cystine excretions. In addition to the havoc this disease is on the kidneys, cystine can often form in and passes through in the ureter and bladder with equally devastating effects. 

As stated before a person who is born with this metabolic disorder should not be compared to a common kidney stone sufferer (the common kidney stones are calcium, struvite, and uric acid)There are many distinctions of Cystinuria to consider. Most common kidney stone sufferers can count the number stones by counting each emergency visit.  Because of the massive amount of cystine excretions, many Cystinurics will never know how many cystine crystals and stones they pass in a week nevermind a lifetime. Cystinurics learn to access their pain to avoid unnecessary emergency visits and spare themselves additional medical costsCystinurics will generally take pain medications when passing stones and access acute pain for 2-3 days and closely monitor their temperature to insure it does not exceed 103° prior to making a trip to the ER.  It would be impractical to seek emergency care for all cystine stones causing pain since many Cystinurics would need to be present at the ER for each urination both day and night. Cystine crystals (crystalluria) and stones are only prevelant in patients born with the rare metabolic disease of Cystinuria. . Because of the genetic composition of cystine, the rare genetic defect of the renal tranport's ability to fully metabolize cystine, and person's inability to avoid amino acids in a reasonable diet plan, the cystine crystals and stones are difficult to treat and impossible to prevent.

PAIN:

Pain management is an all consuming task for Cystinurics. As more understanding of this rare disease  has become evident over the past few years, an increasing number of Cystinurics are opting for a permanent placement of intrathecal pain pumps to combat their daily pain. Some Cystinurics go as far as having the nerves to their kidneys removed.  However, a problem may arise with this option due to Cystinuric's  daily need to access pain levels for emergency care. Also, this surgery  will only address renal colic and not the plateau of other symptoms confronting Cystinurics (please see symptoms below). Insurance does not normally pay the cost of this surgery and finding the right or willing doctor is essential and difficult.  Due to the severity of pain and longevity of chronic pain, a Cystinuric must take care of not over medicating with narcotics.  The problems with many steroid type narcotics is that they may constrict the ureter and thus, cause more pain.  Toradol®  (nonnarcotic) may help a handful of people with great success but can only be taken four days consecutively. Unfortunately, pain medications are needed on daily basis. Because the symptoms of Cystinuria are prominent on a daily basis, Cystinurics may actually have trouble deciphering pain and symptoms from what has become a chronic part of their daily lives since birth. 

* "The term "orphan drug" refers to a product that treats a rare disease affecting fewer than 200,000 Americans. The Orphan Drug Act was signed into law on January 4, 1983. Since the Orphan Drug Act passed, over 100 orphan drugs and biological products have been brought to market.

The intent of the Orphan Drug Act is to stimulate the research, development, and approval of products that treat rare diseases. This mission is accomplished through several mechanisms"
http://www.fda.gov/cder/handbook/orphan.htm

** " [An orphan disease is a disease] which has not been "adopted" by the pharmaceutical industry because it provides little financial incentive for the private sector to make and market new medications to treat or prevent it."

http://www.medterms.com/script/main/art.asp?articlekey=11418

 

SYMPTOMS:

  • Cystine present in urine and/or entire urinary tract.
  • Chronic dysuria (Feeling a frequent urge to urinate, or a burning sensation while urinating)
  • Renal colic: Severe flank pain or back aches on one or both sides. (pain can be acute or chronic) 
  • pelvic or bladder pain (acute or chronic) 
  • Cloudy, bloody or smelly urine.
  • Nausea and/or vomiting
  • Fever(usually low to moderate), chills, and night sweats. (persistent low grade fever associated with cystine crystalluria, infections, and stone passing)
  • Experiencing sudden, unexplained, spasms of debilitating pain (uteric colic or renal)  This will typically originate in the back below the ribcage, and radiate around the abdomen, and sometimes out to the groin area and genitalia.
  • Pains shooting down the leg from the groin. 
  • aching on the balls of the feet (nerve endings)  Overly supportive shoes, like running shoes, may cause nausea.
  • cystine crystalluria (often chronically painful and damaging to tissue in the kidney as well as the entire urinary tract)
  • extreme fatigue, low endurance, and insomnia (perhaps due to the nature of the disease but also the round the clock need for hydration, urination, chronic pain, and depression)
  • daily "run down" feeling 
  • high white blood cell count
  • frequent infections (UTI, bladder, kidney, etc)
  • parenchymal and/or renal failure
  • depression and/or demoralization
  • insomnia and fatigue
  • hydronephrosis
  • a strange taste in mouth (often associated with a  sudden change in creatinine level or symptom of penicillamine)
  • Abdominal/pelvic and  renal tenderness. (“guarding” type pain associated with " cystine crystalluria")

  • increase risk of Kidney cysts

  • retrograde (imbedded) stones and an increase risk of operational misplacement

  • appetite changes

  • medicinally induced headaches or dizziness (mild to extreme)

     

     

  • RESOURCES AND RECOMMENDATIONS FOR FURTHER STUDY:

    CYSTINURIA.ORG: http://cystinuria.org/

    CYSTINURIA SUPPORT NETWORK: http://www.cystinuria.com/

    THE MERCK MANUAL: http://www.merck.com/mmpe/sec19/ch291/ch291b.html

    MEDLINE PLUS:  http://www.nlm.nih.gov/medlineplus/ency/article/000346.htm

    THE OXFORD JOURNAL: http://qjmed.oxfordjournals.org/cgi/content/abstract/40/3/355

    UROLOGY CHANNEL: www.urologychannel.com/

    NEPHROLOGY CHANNEL: www.nephrologychannel.com/

    IBMS INSTITUTE OF BIOMEDICAL SCIENCE: www.ibms.org/

    MEDCAPE: www.medscape.com

    NORD acronym for THE NATIONAL ORGANIZATION FOR RARE DISEASES, INC.:

    http://www.rarediseases.org/search/noddsearch.html

    JAMA: The Journal of the Americal Medical Association: www.jama.ama-assn.org/
    (membership required)
     
    EMEDICINE.COM (Dr. Chandra Shekhar Biyani): http://www.emedicine.com/MED/topic498.htm
     
    ARCHIVES OF INTERNAL MEDICINE:
     
     
    LOUIS C. HERRING LABORATORY &  CO.:  The Recognized World Leader in Stone Analysis for over 60 years
    "We leave no stone unturned!"
     
    Please see the user friendly  link below for the most comprehensive information regarding Cystinuria on the web:
     
     
     
     
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    Table of Contents

    Introduction: Cystinuria
    Crystalluria in Cystinuria
    Understanding Cystinura (An Orphan Disease)
    Symptoms
    Resources and Further Reading................................Page 1
     
    The Orphan Disease
    Cystinuria Versus the Common Kidney Stone
    Risk Assessment
    Drug Information:  Effectiveness and Misconceptions
    Work Cited.............................................................Page 2
     
    Renal Failure
    Cystine Crystalluria and Chronic Pain
    Related Studies on Cystine
    Low-Methionine Diet
    Work Cited
    Additional Reading.................................................Page 3
     
    Cystinuric Blog Page
    What do I know, First Hand, About Cystinuria?
    personal account

     

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    DISCLAIMER:

    This site was created by an actual cystinuric who was frustrated because of conflicting information and the observed lack of understanding being received in her specific case.  This site does not endorse nor in any way condone any treatment option. This site is not meant to serve as anything other than an information resource.  A cystinuric should seek the care of a reliable physician and follow the treatment prescribed by his or her physician and/or medical professionals. 

     

     

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