Cystine Kidney Stones- The Nastiest of All

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Cystine kidney stones form because of a rare inherited genetic disorder called “cystinuria” and they are a particularly nasty lot. Fortunately, this type of kidney stone only impacts about 1-2% of the population (roughly 1 in 7,000 people worldwide).

Autosomal Recessive Inheritance of Cystinuria

Cystinuria is passed down from parents to children through a defect in a specific gene. In order to actually have cystinuria, a person must inherit the gene from both parents (see above photo). Unfortunately, cystinuria is a life-long condition that can be controlled. But, not cured. 

Cystine Kidney Stone

Compared to calcium stone formers, people with cystinuria tend to make larger stones, require more urological procedures, and will start making stones at an earlier age. They also face a greater risk of eventual kidney damage and chronic renal failure compared to calcium stone formers. 1,2,3,4 When you consider all of these factors, you have a recipe for one of, if not the, nastiest kidney stone type out there. 

Cystinuria Impact on Specific Transporters

The primary problem that is caused by cystinuria deals with the reabsorption of the amino acid, cysteine, in the kidneys (see above photo). There are other amino acid reabsorption issues with this disorder as well, including lysine, ornithine, and arginine. However, cystine is the only amino acid that is clinically significant, as it is the only amino acid in the group that will form kidney stones.

Cystinuria Impact on Urinary Cystine Levels

In healthy individuals, a urinary cystine level below 30mg/L is considered normal. For people with cystinuria, cystine levels are chronically well over 250 mg/L, due to the individuals inability to reabsorb cystine because of the disorder. Cystine levels of over 250mg/L mark the point at which kidney stones start to form (see above photo).

According to a recent study, most people with cystinuria get their first kidney stones in their twenties or thirties with 30-40% of people developing cystine stones in their teens. However, some adults have their first cystine kidney stone after age 40. Sadly, children can also get cystine stones.  In fact, according to some research, 8-10% of kidney stones in children are cystine stones.

As with many other kidney stone types (Calcium Phosphate, Uric Acid, and Struvite), urine pH plays a large role in cystine kidney stone formation. For those with cystinuria, cystine solubility is highly impacted by urine pH levels. In normal urine (pH of 6-6.5), cystine solubility (the ability for the body to reabsorb) is very low (250mg/L). However, studies have shown that reabsorption and solubility can be improved by alklizing the urine (pH of 6.5+). Alkalizing the urine can increase solubility to around 500mg/L at a pH of 7.5 and up to 750mg/L at a pH of 8. Please note that achieving urine pH of above 7.5 is very difficult and can also precipitate the formation of calcium phosphate kidney stones, as they are only able to form in alkaline urine (read our blog on Calcium Phosphate Stones HERE). 9

Identification

Most often, cystinuria is found when you have symptoms of a kidney stone. Once passed, the stone is tested to see if it is made out of cystine. A family history of cystinuria can also be an important clue. Other tests may include:

  • Urinalysis: Urine tests can check to see if cystine is in the urine. People without symptoms who have a family history of cystinuria may find this helpful. Additionally, since the cystine molecule (shown above) contains sulfur, the urine of hyper-cystinuric individuals may have a rotten egg odor.
  • Imaging: Imaging tests can be used to locate stones in the body:
    • Ultrasound: uses a device to bounce safe, painless sound waves off organs and create an image of their structure.  Many healthcare providers feel that this is the best screening test to find stones.
    • Computerized Tomography (CT) Scans:  This method uses X-rays to create images and look for stones inside the kidneys. CT scans without contrast are the “Gold Standard” for diagnosis of kidney stones and will demonstrate cystine stones clearly. Plain X-rays of the abdomen will not show cystine stones very well, as they’re only faintly visible due to their “ground glass” appearance. 9

At the present time, genetic testing for the defective gene is not often used to find cystinuria. But, it can play a role in diagnosis if needed.

 

Surgical Treatment

Surgical treatment of cystine stones is similar to that of other kidney stones. However, cystine kidney stones are notoriously resistant to extracorporeal shock wave lithotripsy (ESWL). As a general rule of thumb, ureteroscopy with laser lithotripsy is preferred for most cystinuria patients with obstructing cystine stones that require surgery.

Total removal of all cystine stones and fragments has demonstrated reduced recurrence rates and better preservation of renal function. Fortunately, surgery has not demonstrated any measurable decrease in overall renal function. 12-14

 

Medical Management

Acceptable levels of urinary cystine are 250 mg/L or less at a urinary pH of 6.5 to 7. This level can often be reached through an increased fluid intake and urinary alkalinization. The use of thiol-based medications to reduce urinary cystine levels is discouraged unless hydration therapy and alkalinization treatment are insufficient to achieve the desired "optimal" cystine concentration levels (less than 250 mg/L) at an acceptable pH (6.5 to 7). 

A sustained urinary pH of 7.5 can be used to dissolve existing cystine stones. Some experts have recommended even lower cystine concentrations of 150 mg/L and possibly even lower at 90 mg/L as "optimal." 9

Increase Water Intake

Hydration is usually the first step in medical management. Increasing fluid intake sufficiently to reliably generate 2.5-3L or more of urine per day is often necessary. The goal of this increase in water intake is to dilute the urine sufficiently to get the urinary cystine content as close to the less than 250 mg/L recommended concentration level as possible. For most individuals, this will translate to about 3-4L (about a gallon) worth of water per day (just like we mentioned in our previous blog, 4 Keys to Naturally Passing Kidney Stones)

Since some cystinuric patients can generate up to 1400 mg of cystine per day, hydration alone may not be sufficient, but it is always the first step in management. Up to one-third of cystine stone patients can manage their stone recurrences with fluid management. Optimal hydration will depend on the patient's cystine excretion. 9

In addition to increased water intake, alkalinization of the urine can help prevent cystine stone formation and also dissolve existing cystine stones. To prevent cystine kidney stones, the urinary pH should be targeted at 7.0 to 7.5, but to dissolve cystine stones, a urinary pH higher than 7.5 needs to be maintained. However, at this high pH level (above 7.5), calcium phosphate stones could start to be a concern, as they form in alkaline urine.  

In such cases, hypercalciuria (elevated calcium in urine) needs to be controlled tightly with diet. Eating more fruits/vegetables and reducing meat consumption can make urine less acidic. Even reducing salt intake has been shown to help keep cystine stones from forming. Mineral water, citrus juices, and citrate supplements can help increase pH level, too.

For the best results, naturally occurring citrates (fresh lemon/lime juice) are always recommend over synthetic (potassium citrate, magnesium citrate, etc). The herb Chanca Piedra can also be added to the diet as a booster, as it increases urinary citrate which inhibits the formation of all kidney stone types.

Sodium bicarbonate can also be used to help with pH issues, but it tends to have a relatively short-term alkalinizing effect, and the extra sodium intake may increase urinary cystine excretion. High animal protein diets are also discouraged in cystinuric patients for the same reason. 9

When conservative measures as outlined above are insufficient after a 3-month trial period, a thiol-based drug regimen is usually the next step in active cystine stone formers. 9

Cystine Molecule Model

Thiol-Based Agents

Cystine is composed of 2 cysteine molecules bound together by a disulfide bond. Thiol-based drugs have sulfhydryl groups that can reduce this disulfide bond producing a mixed cysteine disulfide compound that is far more soluble than the original cystine molecule. As a general guide, most patients with a 24-hour urinary cystine excretion of 500mg or more are likely to need a thiol medication in addition to hydration therapy and alkalization. 9

Thiol-based treatment is also thought to have the extra benefit of possibly making cystine stones more amenable to ESWL treatment. This may occur because of the mixing of calcium phosphate along with the cystine creating a more fragile stone that is more easily fragmented with ESWL therapy.

Outlined below are a few of the different thiol-based agents currently available:

  • Penicillamine, a penicillin derivative, was the first thiol drug used for cystinuria. Penicillamine-cysteine disulfide is 50 times more soluble in urine than cystine. Each 250 mg penicillamine tablet can reduce urinary cystine levels by about 75 mg to 100 mg per day. 
    • The problem with penicillamine is that there is a high incidence of side effects including fever, rash, loss of taste, arthritis, leukopenia, aplastic anemia, gastrointestinal (GI) disturbances, renal membranous nephropathy with proteinuria, and pyridoxine deficiency. 
    • The incidence of significant side effects is about 50% which limits long-term compliance. In one study, almost 70% of patients discontinued the drug due to adverse effects. For these reasons, penicillamine use is limited in favor of other thiol-based drugs. 16
  • Tiopronin (Thiola, alpha-mercaptopropionylglycine, or alpha-MPG) is a second-generation thiol drug that works similarly to penicillamine but is roughly 30% more effective with significantly fewer side effects. It was approved for use in the United States in 1988, so there is ample experience with the medication. 
    • The typical dose is 300 mg three times per day. Long-term compliance is about 70%. For these reasons, tiopronin is currently the thiol drug of choice for cystinuria when hydration and urinary alkalization therapy fail to achieve optimal cystine concentration levels at an acceptable pH. 17
  • Captopril is an ACE inhibitor normally used for hypertension, but it is also a thiol-based drug that can form captopril-cysteine mixed disulfides that are highly soluble, in cystinuric patients. 
    • While safe with few side effects, captopril's clinical effectiveness in cystinuric stone forming patients is uncertain as various studies provide conflicting results. It should be considered a reasonable treatment option in cystinuric patients who are also hypertensive. 18
  • Bucillamine is a third-generation, thiol-based drug that is currently available only in Japan and South Korea and is approved only for use in rheumatoid arthritis. 
    • As a di-thiol compound, it would theoretically be more effective than tiopronin and better tolerated since lower dosages of the drug would be needed. 
    • Experience in Asia has shown a low toxicity profile, and phase-2 studies are currently underway in the United States to determine its potential clinical usefulness in treating hyper cystinuria.

 

Summary

Treatment for cystinuria starts with diet (low meat protein + low sodium) and hydration sufficient to generate 2.5-3L of urine daily or more. Urinary alkalinization with mineral water, fruit juices (naturally occurring citrates), and potassium citrate (synthetic) will also greatly increase cystine solubility. Anti-lithic herbs such as Chanca Piedra will also add a boost in prevention due to their ability to naturally boost levels of citrate in urine. 

The goal is to achieve a cystine concentration of 250 mg/L or less at a pH of at least 6.5. "Optimal" cystine level is generally considered to be 150 mg/L or less, but some reports suggest that a cystine concentration goal of 90 mg/L is "optimal."  If this is not achievable or possible for any reason, (tolerability, compliance issues, side effects), then the use of a thiol-based cystine lowering medication is warranted.

Currently, tiopronin (Thiola) is the recommended thiol medication of choice based on its efficacy and reduced side effect profile. Long term studies of cystinuria patients followed for 21 years have shown that the best preservation of renal function and the lowest recurrence rates are found in those with early medical management of cystinuria along with complete surgical stone removal. 21

 

References

1 Reinstatler L, Stern K, Batter H, Scotland KB, Ardekani GS, Rivera M, Chew BH, Eisner B, Krambeck AE, Monga M, Pais VM. Conversion from Cystine to Noncystine Stones: Incidence and Associated Factors. J. Urol. 2018 Dec;200(6):1285-1289. 

2 Yang Y, Albanyan H, Lee S, Aloysius H, Liang JJ, Kholodovych V, Sahota A, Hu L. Design, synthesis, and evaluation of l-cystine diamides as l-cystine crystallization inhibitors for cystinuria. Bioorg. Med. Chem. Lett. 2018 May 01;28(8):1303-1308. 

Usawachintachit M, Sherer B, Hudnall M, Tzou DT, Taguchi K, Hsi RS, Stoller M, Chi T. Clinical Outcomes for Cystinuria Patients with Unilateral Versus Bilateral Cystine Stone Disease. J. Endourol. 2018 Feb;32(2):148-153.

Friedlander JI, Antonelli JA, Canvasser NE, Morgan MSC, Mollengarden D, Best S, Pearle MS. Do Urinary Cystine Parameters Predict Clinical Stone Activity? J. Urol. 2018 Feb;199(2):495-499.

Shen L, Cong X, Zhang X, Wang N, Zhou P, Xu Y, Zhu Q, Gu X. Clinical and genetic characterization of Chinese pediatric cystine stone patients. J Pediatr Urol. 2017 Dec;13(6):629.e1-629.e5.

Gres AA, Nitkin DM, Juraha TM, Sivakow AA. [Cystine as a risk factor of the stone formation in kidney: the reference value range of urinary excretion, the stage diagnosis of cystine metabolism disorder]. Urologiia. 2016 Aug;(4):10-14.

7 Streeper NM, Wertheim ML, Nakada SY, Penniston KL. Cystine Stone Formers Have Impaired Health-Related Quality of Life Compared with Noncystine Stone Formers: A Case-Referent Study Piloting the Wisconsin Stone Quality of Life Questionnaire Among Patients with Cystine Stones. J. Endourol. 2017 Apr;31(S1):S48-S53. 

Obaid A, Nashabat M, Al Fakeeh K, Al Qahtani AT, Alfadhel M. Delineation of cystinuria in Saudi Arabia: A case series. BMC Nephrol. 2017 Feb 06;18(1):50. 

Courbebaisse M, Prot-Bertoye C, Bertocchio JP, Baron S, Maruani G, Briand S, Daudon M, Houillier P. [Nephrolithiasis of adult: From mechanisms to preventive medical treatment]. Rev Med Interne. 2017 Jan;38(1):44-52.

10 Andreassen KH, Pedersen KV, Osther SS, Jung HU, Lildal SK, Osther PJ. How should patients with cystine stone disease be evaluated and treated in the twenty-first century? Urolithiasis. 2016 Feb;44(1):65-76.

11 Nakanishi Y, Hanasaki T, Yo T, Shiraishi Y, Togo Y, Taoka R, Suzuki T, Higuchi Y, Kanematsu A, Hashimoto T, Doi Y, Nojima M, Yamamoto S. [Impacted ureteral stents with cystine encrustation in cystinuric patients : report of two cases]. Hinyokika Kiyo. 2013 Oct;59(10):651-5. 

12 Rousaud F, Gracia S, Palacín M, Nunes V, Millán F, Oliver A, Rousaud A. [Cystinuria and cystine kidney lithiasis. Diagnosis and therapeutic approach]. Arch. Esp. Urol. 2001 Nov;54(9):989-96.

13 Sfoungaristos S, Hakim R, Katz R, Gofrit ON, Landau EH, Yutkin V, Pode D, Duvdevani M. Cystine stones: a single tertiary center experience. J. Endourol. 2015 Mar;29(3):362-6. 

14 Nakagawa Y, Coe FL. A modified cyanide-nitroprusside method for quantifying urinary cystine concentration that corrects for creatinine interference. Clin. Chim. Acta. 1999 Nov;289(1-2):57-68.

15 Sterrett SP, Penniston KL, Wolf JS, Nakada SY. Acetazolamide is an effective adjunct for urinary alkalization in patients with uric acid and cystine stone formation recalcitrant to potassium citrate. Urology. 2008 Aug;72(2):278-81.

16 Moore SL, Somani BK, Cook P. Journey of a cystinuric patient with a long-term follow-up from a medical stone clinic: necessity to be SaFER (stone and fragments entirely removed). Urolithiasis. 2019 Apr;47(2):165-170. 

17 Joly D, Rieu P, Méjean A, Gagnadoux MF, Daudon M, Jungers P. Treatment of cystinuria. Pediatr. Nephrol. 1999 Nov;13(9):945-50.

18 Fattah H, Hambaroush Y, Goldfarb DS. Cystine nephrolithiasis. Transl Androl Urol. 2014 Sep 01;3(3):228-233. 

19 Cohen TD, Streem SB, Hall P. Clinical effect of captopril on the formation and growth of cystine calculi. J. Urol. 1995 Jul;154(1):164-6. 

20 Sahota A, Tischfield JA, Goldfarb DS, Ward MD, Hu L. Cystinuria: genetic aspects, mouse models, and a new approach to therapy. Urolithiasis. 2019 Feb;47(1):57-66.

21 Hu L, Yang Y, Aloysius H, Albanyan H, Yang M, Liang JJ, Yu A, Shtukenberg A, Poloni LN, Kholodovych V, Tischfield JA, Goldfarb DS, Ward MD, Sahota A. l-Cystine Diamides as l-Cystine Crystallization Inhibitors for Cystinuria. J. Med. Chem. 2016 Aug 11;59(15):7293-8. 

*Source: StatPearls Publishing LLC - Authors: .

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