What are cystine kidney stones?Cystine kidney stones are renal calculi formed from the excessive cystine (an amino acid) present in the urine.
AdvertisementsIn normal individuals only a relatively small amount of cystine is excreted in the urine. Cystine stones rarely form when the urine excretion of this amino acid is less than 150 mg per day. The amount of excretion of cystine and the dibasic amino acids, including ornithine, arginine and lysine, is regulated by the renal cystine transport.
Urine production is a complex process. More than 1200 ml of blood passes through the kidneys per minute. Each kidney has about one million nephrons. Each nephron is the primary functional unit of kidney and has a filtering system known as glomerulus. The renal tubule is the reabsorption, secretion and collecting system, through which the filtered liquid passes. Except for very large macromolecules and blood cells, the blood plasma is filtered into the tubule. 80% of the filtrate is reabsorbed at the proximal tubule by active and passive absorption. Several separate luminal transmembrane channels function to reabsorb and transport back minerals, vitamins, amino acids etc into the bloodstream.
Cystine kidney stones causesCystine stones are caused by cystinuria. Cystinuria is an inherited autosomal recessive disease. It causes defective renal tubular reabsorption of cystine and the three dibasic amino acids arginine, lysine and ornithine. It also affects the intestinal transport of these amino acids. Cystinuria patient has a lifelong risk of cystine stone formation because, unlike dibasic amino acids, cystine has low solubility in urine. Further in acidic urine, cystine is less soluble and precipitates faster, forming the calculus. Infections and obstructions in the urine flow can also give rise to formation these calculi.
Mutations within the SLC3A1 and the SLC7A9 genes are known to be associated with cystinuria. Cystinuria being an inherited recessive disease, the patient has to get the mutant genes from both the parents to become a cystinuric. Erik.Fjellstedt et al had reported that apart from the SLC3A1 and the SLC7A9 genes,
- an additional gene or genes participate in the urinary cystine reabsorption in the cystinuric patients who currently are without a full genetic explanation for their disease.
Types of cystinuriaEarlier phenotypically distinctive groups of cystinuria, referred to as types I, II, and III were described. However in this classification it is cumbersome to differentiate type II cystinuria from type III. The type II homozygotes lack intestinal cystine absorption. With the identification of multiple mutations in the SLC3A1 and the SLC7A9 genes associated with the disorder, a genotypic classification of cystinuria has been introduced. Certain distinctive inheritance patterns are becoming clear.
The type I form of cystinuria is found to be completely recessive. Heterozygote individuals with type I mutations do not show any clinical manifestations. However the non-type I form (types II and III) of cystinuria is incompletely recessive. Heterozygote individuals with non-type I mutations have varying levels of urinary cystine excretion and even form cystine stones.
Cystine kidney stones symptomsThe individuals with these calculi, experience all the typical symptoms associated with renal calculi. Blood in the urine (hematuria), nausea, pain in the flanks, renal colic, obstruction to urine flow, urinary tract infections, pyelonephritis, renal insufficiency and end-stage kidney disease are some of the symptoms.
Cystine kidney stones diagnosisThe key finding in diagnosis is the presence of large amount of cystine in the urine. As cystine is a sulfur containing amino acid, the urine may have the characteristic odor of rotten eggs. Urinalysis may show typical hexagonal crystals. Sodium cyanide–nitroprusside test is done for qualitative determination of concentrations followed by ion-exchange chromatographic quantitative analysis for confirmation. There are also increased urinary levels of three other amino acids, lysine, arginine, and ornithine. These kidney stones may not be visible on most x-rays, CT's, and ultrasounds.
Cystine stones preventionAs cystine stone formation is a lifelong problem, the main focus must be on the prevention rather than the treatment.
- Hydration, urinary alkalinization, urine dilution and increasing urine output are of prime importance.
- The patient may be encouraged to take much more than one liter of water per twenty kilograms of body weight in a day. Additional water is necessary to compensate losses due to heat and sweating.
- For avoiding nocturnal formation and aggregation of crystals, the patient is advised to take 300 ml of water overnight, as well as to void urine at least twice during the night.
- Urine alkalinisation is to be maintained to dissolve existing calculi as well as to increase the solubility of cystine. Oral alkalinisation treatment with potassium bicarbonate is done to maintain the urine pH between 7.5 and 8.0. However oral alkalinisation treatment must be closely monitored, especially in patients with hypertension, impaired kidney function, diabetes and in those on diuretics.
- The dietary restriction of the metabolic precursor of cystine, the amino acid methionine, may restrict the cystine excretion. Restriction of methionine-containing foods (milk, meat, eggs, etc.) results in a decrease in total urinary cystine excretion. However the total protein requirement of the body cannot be compromised. Hence dietary restriction may not work well for many patients, especially children.
- Increase in sodium intake has a direct effect on the increase in cystine excretion. Hence sodium intake has to be restricted.
Cystine kidney stones treatmentMedication is available for decreasing the total urinary excretion of cystine. Penicillamine and alpha-mercaptoproprionylglycine (tiopronin or Thiola) are the usual medicines prescribed for decreasing the excretion of the amino acids. These are chelating agents that combines with cystine to form a soluble disulfide complex. However they carry the high risk of allergy, arthralgia, leukopenia, gastrointestinal intolerance, nephritic syndrome and toxicity. Hence these medications may be considered as a supplemental effort to hydration and urinary alkalinization. Though acetazolamide helps in rapid stone dissolution, it has adverse effects.
Surgical options are available for removing kidney stones that are negatively responding to the above non-surgical treatments. Extracorporeal shockwave lithotripsy, retrograde endoscopic lithotripsy and extraction, ureteroscopy, percutaneous nephrostolithotomy, percutaneous nephrolithotomy, combination therapy and open surgery are the surgical options available for removing cystine kidney stones.
4.Fjellstedt E, Harnevik L, Jeppsson JO, Tiselius HG, Söderkvist 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 Dec;31(6):417-25. Epub 2003 Oct 25.
5.Worcester EM, Coe FL, Evan AP, Parks JH. Reduced renal function and benefits of treatment in cystinuria vs other forms of nephrolithiasis. BJU Int. 2006 Jun;97(6):1285-90.
6.Trinchieri A, Montanari E, Zanetti G, Lizzano R. The impact of new technology in the treatment of cystine stones. Urol Res. 2007 Jun;35(3):129-32. Epub 2007 Apr 18.
7.Kamran Ahmed, Prokar Dasgupta, Mohammad Shamim Khan. Cystine calculi: challenging group of stones. Postgrad Med J. 2006 Dec; 82(974): 799–801.
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