Cystine Kidney Stones

Cystine stone crystals in urine

Classic “stop sign” crystals seen in the urine of patients with cystine urinary stone disease are illustrated.  Most cystinurics do not have these crystals in their urine but when they are present they confirm the diagnosis.

WHAT ARE CYSTINE STONES?

Cystine stones account for 1-2% of all renal stones and 6-8% of calculi in children.  Unlike most stones, they are caused by a genetic mutation and are inherited. This condition is called “cystinuria” and individuals can inherit one gene (heterozygous) or two genes (homozygous). There is no sexual predilection and patients may present at any age. The primary symptom of having cystinuria is the formation of urinary calculi. Stones may be present in single, multiple, or large staghorn configurations. Pure cystine stones are not easily visible on plain x-rays due to their sulfur content.

DIAGNOSIS

A strong family history of kidney stones, development at a young age, or recurrent stone disease are suggestive of the diagnosis.  Hexagonal “stop sign” crystals discovered during microscopic examination of urinary sediment are highly indicative of having the disease, but are found in only 17-26% of patients with homozygous cystinuria. Cystine stones are amber in color.  Stone analysis will confirm the diagnosis.

Cystine is an amino acid and normal individuals excrete low amounts in the urine (18 milligrams cystine/gram creatinine). Simple heterozygous adults (those with one inherited gene) usually excrete <150 mg/g of creatinine.  Most homozygous cystinurics (with the more severe two gene inheritance), in comparison, excrete >250 mg/g creatinine.

The limited solubility of cystine is responsible for spontaneous crystallization and subsequent stone formation when it is present in high concentrations. Urinary pH, or the acidity, does have a profound effect on cystine solubility, however, and manipulating the pH is one of the mainstays of therapy to dissolve and preventive cystine stones.

PHYSIOLOGY

Cystinuria is caused by a genetic mutation that results in abnormal (decreased) small bowel absorption and kidney reabsorption of cystine and three other amino acids:  ornithine, lysine, and arginine.  Three types of genetic mutations can lead to cystinuria.

Urinary levels of cystine are elevated in patients with cystinuria despite decreased bowel absorption because of the kidney abnormalities allow cystine to “leak” into the urine.  The primary source for urinary cystine is due to the body’s breakdown of its precursor, methionine, an amino acid present in many foods.

MEDICAL MANAGEMENT

Cystinuric patients can develop stones with amazing rapidity.  Surgical treatment alone is destined to failure.  Patients and their families also require genetic counseling, medical management, and regular followup evaluations.

Medical therapy is directed at dissolving existing calculi and preventing formation of new calculi.  Four methods of achieving these goals have been utilized:  (1) increasing fluid intake to decrease the relative concentration of urinary cystine; (2) altering urinary pH to increase cystine solubility; (3) decreasing the amount of urinary cystine by dietary modifications; and (4) binding urinary cystine with medications to form more soluble compounds.

Urinary cystine concentration can most simply and effectively be lowered by increasing urinary volume.  Fluid intake adequate to keep the urinary concentration of cystine below its solubility level throughout the day is the goal.  This goal is difficult to achieve in homozygous patients and requires almost continual fluid intake throughout the day and repeated intake at night to prevent nighttime increases in cystine urine concentration.  Patients should be encouraged to drink fluid prior to going to bed and at least once during the night (total intake 2.5-4 liters daily).

Alkalinization takes advantage of the pH dependence of cystine solubility.  An elevated urinary pH can be achieved by divided-dose administration of alkali medications (citrate, bicarbonate, or mixed preparations).  Potassium containing formulas are preferable to sodium containing preparations because they do not enhance calcium and cystine stone formation.  Citrate may be preferred to bicarbonate because of its relatively prolonged duration of action. Urinary alkalinization above a pH of 7.5 may increase the tendency for calcium stone formation (especially calcium phosphate) due to the tendency of these stones to form in a non-acidic high pH environment.  Patients can be instructed to adjust the dose of medications using home urine pH paper tests (similar to home pregnancy tests) to maintain their urinary pH between 7.2 and 7.5. Methionine is a precursor of cystine and dietary restriction in theory could lead to decreased cystine production and urinary concentrations.  Rigid methionine dietary restriction is very difficult however and of limited benefit.

Methods to increase cystine solubility by binding it to various medications have been developed.  The chemical structure of cystine, with its disulfide bond joining two cysteine molecules, makes it amenable to this approach.

Captopril can form a disulfide bond with cystine and render it more soluble.  This thiol-cysteine mixed disulfide is 200 times more soluble than cystine.  The effectiveness and mechanism of captopril therapy remains controversial.

D-penicillamine and alpha mercaptopropionylglycine (a-MPG) have documented efficacy in reducing cystine excretion.  They both undergo disulfide exchange with cystine to form more soluble mixed disulfide compounds.  The disulfide exchange reaction is facilitated by an alkaline urinary pH.  Both D-penicillamine and a-MPG appear to decrease renal excretion of cystine in addition to increasing cystine solubility.  Urinary cystine excretion frequently falls below 200 mg/g creatinine.  Over 50% of patients discontinue D-penicillamine due to severe adverse affects. a-MPG is better tolerated by most patients.  Adverse affects occur in 75% of patients but are generally less severe. a-MPG has similar effectiveness to D-penicillamine.  Patients who fail medical therapy or who are symptomatic require surgical treatment.

SURGICAL MANAGEMENT

ESWL

ESWL has a reduced success rate for the treatment of cystine stones.  The organic nature and uniform structure of pure cystine make them the least fragile of all urinary calculi.  Cystine stones less than 1.5 cm respond more favorably to ESWL than stones larger than 1.5 cm. These stones may require substantially more shocks than equivalent sized non-cystine calculi.

Ureteroscopic Management

Small cystine calculi in the distal ureter usually can be managed easily with ureteroscopic basketing and extraction.  Electrohydraulic and ultrasonic lithotripsy, older technologies, often failed due to the hardness of cystine calculi.  Laser lithotripsy was also initially frequently ineffective but its success has improved with the current generation of holmium lasers, which are able to successfully fragment these stones.

Percutaneous Management

Percutaneous surgery should be considered in patients with complex cystine stones, a large stone burden, or stones that have failed medical management, ureteroscopy, or ESWL.  Cystinuria is a lifelong disorder requiring frequent intervention and thus open surgery should be avoided.

Lithochemolysis

Cystine calculi can be dissolved by percutaneous and retrograde direct irrigation.  The solutions used are based upon the same principles as for oral dissolution therapy:  creating an alkaline environment to increase cystine solubility and causing a disulfide exchange reaction to create a more soluble compound.  Percutaneous irrigants include N-acetylcysteine, N-acetylcysteine with bicarbonate, bicarbonate, and tromethamine-E.  The success rate is limited in the presence of mixed cystine stones, since calcium and struvite components will not dissolve and the alkaline environment may actually promote hydroxyapatite and struvite growth.

Combination Therapy

In many patients with a large stone burden, PNL, ESWL, and chemolysis will all likely be required to achieve a stone free status.  Every attempt should be made to render a patient stone free in order to reduce long-term problems.  Recurrences are frequent even after a stone free status is achieved, highlighting the importance of medical therapy and frequent follow up evaluation to monitor progress.

 

 

 

About Dr. Marshall Stoller

Marshall Stoller, MD, is a Professor of Urology at University of California at San Francisco, in San Francisco, CA
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12 Responses to Cystine Kidney Stones

  1. azadeh says:

    I have cystinuria. Can I marry and have children without cystinuria? How I can realize my partner doesn’t have this gene?is there any test ? And is it a common test. I think my partner may accept this problem Very hardly. Is it a complicated problem for getting married?

  2. Bethany says:

    I found out at 5 years old I had 32 kidneys stones, they went through my back to remove the stones, since then I’ve had 28 surgeries, had my last surgery in April, then in may I found out that I’m pregnant. I’m now 13 weeks pregnant and started having pains today, I’m about to go to the er, concerned. Anybody have cystine stones while pregnant?
    Please, any info?

  3. Jugal Kishore says:

    Hi,
    I have cystine stone in my both kidneys. One side I have operated in AIIMS. In a test of urine 24 hours for cystine found that my cystine in 3030 higher than normal range. Please advise how to control it.
    Jugal Kishore

  4. FreyaGPC says:

    Greetings!
    I’m just curious, will alkaline water help people from forming cystine stones? (33% calcium, 22%oxalate, 42%cystine)
    can you tell me more about the composition of these elements?
    Thank you, and more power!

  5. Corey Haley says:

    I have no known family history of stones (known of my relatives have had them) I out of the blue at 29 started having kidney stones. The stone’s analysis shows it is cystine. My question is are there any other reasons why I would have a cystine stone other than genetics? Most of what i read is people having tons of stones from a young age, in my case over the last two years I have had 15 stones. Could it be stress related? Or is it only caused by this genetic issue? Additionally does climate affect cystine stone formation? Thank you

    • Dr. Mike Nguyen says:

      Cystinuria is usually inherited from your parents. Because it is a “recessive” gene, a person usually has to inherit it from both parents to notice development of stones. Individuals who only inherit one copy usually will not form stones (they will have elevated cystine levels in their urine, just not enough to form stones). Therefore, if each of your parents has one copy of the cystinuria gene, they themselves may not have stones but would have a 25% chance of having a child together who would inherit two copies of the gene. Spontaneous mutations in the genes, without inheritance from one or both parents, can also occur although this is less likely.

      Cystine stones would not be caused by stress alone but stone formation in cystinuria patients can be affected by fluid intake and dehydration, both of which can be impacted by stress or climate.

  6. brendan jackson says:

    I have cystineuria and am struggling to control it I have tried most things. I average one stone approximately 14mm smallest to the 3.5cm that blocked my left kidney. I have put a stop to my treatment. As you seam to know alot more that most was wondering if I keep refusing treatment, how many long would you estimate I have left?

    • Dr. Marshall Stoller says:

      Cystinuria is a frustrating disease. There are times when stones are silent
      and do not form and other times when stones recur quite frequently. The
      good news is that it is extremely rare that cystine stone formers will
      progress to require hemodialysis or renal transplantation.

      We also have published data showing that cystinurics frequently form stones
      on just one side. This has been well established. One may try to sleep
      such that the stone side is more commonly on the “up” side rather than the
      down side.

      Bottom line: you need to drink lots of water – 24-hours per day. We
      recommend having a few additional alarm clocks to awaken you in the middle
      of the night to ensure that you void and re-hydrate.

  7. Deirdre says:

    How common is it for a patient with homozygous cystinurea to never form a stone?

    • Dr. Mike Nguyen says:

      Because of the relative rarity of cystinuria, it is hard to find reliable, long term data on the risk of stones. A review of the literature found the following:

      Most but not all patients with homozygous cystinuria (carrying two copies of the abnormal gene) appear to develop stones throughout their lifetime. A study by the International Cystinuria Consortium reported that 6% of individuals with homozygous cystinuria did not produce stones. The age at which individuals first formed stones also varied, with many experiencing stones between 11 and 20 years of age but with some forming stones before the age of 3.

      Complicating matters, cystinuria is classified into types A, B, and AB, depending on the specific combination of two known inheritable genes (SLC3A1 and SLC7A9) that can cause the disease. The risk and age of onset of developing stones varies with which type an individual has.

      References:
      Pathophysiology and Treatment of Cystinuria. Chillaron et al. Nature Reviews Nephrology. 2010.
      Cystinuria Subtype and the Risk of Nephrolithiasis. Goodyer et al. Kidney International. 1998.

      • Tyler Parker says:

        i am a 20 year old female and i got my first kidney stone when i was 18 years old and ive had them ever since. i get them all the time and the only fluid i drink is water. i also have a lot of family history history with kidney stones on both sides of my familes. ive had the shock wave procedure once but they came back months later. my kidneys hurt all the time and if i throw up because of sickness not related to kidney pain it causes major pain in them even if they werent hurting before. how do i know if i have the Cystine stones?

        • Dr. Mike Nguyen says:

          Cystine stones are confirmed with chemical analysis of the actual stone or with 24 urine collection testing for abnormal levels of cystine in the urine.

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