Cystine stones E72.0+N22.8*

In 1810, Wollaston was the first to describe a cystine stone excreted in the urine (Hoffmann 2014).

Cystine stones represent the manifestation of a disease in which - due to an excess of cystine - stones form in the urogenital tract. Cystine stones have a typical greyish/yellow colour and are hard (Kuhlmann 2015 / Keller 2010).

Cystine stones belong to the group of genetically determined stones (Kuhlmann 2015). They are caused by cystinuria and can occur as homozygous (so-called classical cystinuria [Dötsch 2017]) and heterozygous forms.

In heterozygotes, one differentiates between two variants:

• Type 1- heterozygote: In this case, the excretion pattern for four amino acids (see "Etiopathogenesis") is normal.
• Non-type 1 heterozygotes (formerly type II and III): In this type, moderately elevated levels of all four amino acids are found (Kasper 2015).

Cystine stones are rare, accounting for approximately 1 % - 2 % of all kidney stones (Kasper 2015). However, they are the most common genetic stone disease with a prevalence of approximately 1: 7,000 (in homozygotes). Approximately 10% of childhood lithiasis are cystine stones (Weigert 2018).

Cystinuria with the formation of cyst stones is an autosomal recessive disease. It can be caused by mutations on 2 different chromosomes (chromosome 2 and 19) (Kuhlmann 2015).

It involves a defect in the membrane carrier proteins in the intestinal cells and in the proximal tubule system of the kidneys. This results in decreased reabsorption of the following dibasic amino acids (Kasper 2015):

• Cystine
• Lysine
• Ornithine
• Arginine

The accumulation of the dibasic amino acids in the urine leads to precipitation with formation of typicalhexagonal cystine crystals (Kasper 2015).

In homozygotes of both variants (see "Classification" above), there is a significantly increased excretion of the above-mentioned amino acids. Type 1 heterozygotes show normal excretion patterns for amino acids, while non-type 1 heterozygotes excrete moderately elevated levels (Kasper 2015).

In the homozygous form, recurrent stone disease begins in childhood. In heterozygotes type 1 (see "Classification"), nephrolithiasis usually occurs after the age of 10, in non-type 1 in approx. 79 % already before the age of 10 (Dötsch 2017).

The typical symptoms are:

• Occurrence of colic as soon as the stone passes a physiological constriction (such as the outlet of the renal pelvis, the vascular junction of the ureter or the ureterostium) or becomes obstructively lodged at a site of the draining urinary tract (Kuhlmann 2015).

Colic can result in the following symptoms:

• sudden onset of the strongest swelling pain in the area of the flank with radiation:
• into the upper abdomen or back in case of obstruction in the proximal part of the ureter
• in the middle and lower abdomen in case of obstruction at the pelvic junction of the ureter
• in the groin, the ipsilateral testis or the ipsilateral labia in case of an obstruction in the lower part of the ureter.
• haematuria: in 90 % there is at least microhaematuria, macrohaematuria is found in 1 / 3 of the cases
• Dysuria
• bladder amenorrhoea
• motor restlessness of the patient (typical symptom)
• nausea
• vomiting
• reflexive subileus with retention of stool and wind (Kasper 2015 / Herold 2020)

The diagnosis of cystinuria can be made by the following characteristics or findings:

• detailed anamnesis
• occurrence of nephrolithiasis already in childhood
• high activity of lithiasis before appropriate therapy
• detection of hexagonal cystine crystals (preferably in concentrated morning urine; normal cystine excretion is up to 30 mg / d)
• increased excretion of the four dibasic amino acids (see "Etiopathogenesis")
• Analysis of excreted concretions (Kuhlmann 2015)
• positive nitroprusside test (see "Laboratory") (Kasper 2015)

Sonography: Ultrasound is the first choice both in the acute situation of colic and in routine examinations (Seitz 2018).

• Detection of calculi (small stones are sometimes not visible on ultrasound).
• Renal congestion
• Ectasia of the renal pelvis (Herold 2020).

Radiograph:

• Cystine stones (may be faintly shadowing [Sigel 1993]).
• Shadowing if high in sulfur (Kuhlmann 2015).

Computed tomography: CT can be used as a low-dose CT without contrast agent if no calculus is detectable on sonography and also if complications occur in the setting of lithiasis. CT also provides information on stone composition and any inflammatory reactions (Kuhlmann 2015). Sensitivity and specificity are close to 99% (Herold 2020).

For further diagnostic measures, see. Nephrolithiasis.

Urinalysis:

• Urine test strips
• Micro- or macrohaematuria
• Leukocyturia
• Nitrite
• Protein
• Glucose
• Sediment (bacteria, crystals)
• Creation of a culture for germ differentiation and creation of an antibiogram
• Analysis of departed concrements
• 24h- collection urine:
  • Uric acid (elevated in urate stones)
  • Calcium (elevated in primary hyperparathyroidism)
  • Oxalate
  • Cystine
  • Phosphate
  • Dihydroxyadenine (DHA) in children (Kasper 2015 / Kuhlmann 2015 / Schmelz 2006).

Blood test:

• Blood gas analysis
• small blood count
• Electrolytes
• CRP
• Creatinine
• Urea
• Uric acid
• PTT and INR for probable intervention (Seitz 2018).
• -Qualitative detection of cystine

Sodium nitroprusside test (also called Brand test): This test allows a qualitative detection of elevated cystine or homocystine levels in urine. Values of > 75 mg / l result in a cherry-red to violet coloration of the urine. (Kasper 2015 / Gressner 2019)

Quantitative detection of cystine: The quantitative determination of amino acids is performed by HPLC (High Performance Liquid Chromatography) .This test allows differentiation between homozygotes and heterozygotes. The normal cystine excretion is up to 30 mg / d. In homozygotes, amounts of 600 mg - 1,800 mg of cystine can be excreted daily. Preferably, one should use concentrated morning urine for the test, which was previously alkalinized - to avoid precipitation of cystine - with bicarbonate to a pH- value of > 7.5 (Kuhlmann 2015 / Kasper 2015 / Seitz 2018).

• Urinary tract infection (UTI), which can lead to urosepsis. UTI is the most important and also the most frequent complication of lithiasis (Herold 2020).

Early symptoms of urosepsisare (Schmelz 2006):

• Tachypnea (> 20 breaths / min)
• Tachycardia (> 90 beats / min)
• hyperthermia (> 38 ° C)
• Hypothermia (< 36 ° C, alternating with fevers)
• Urinary tract infection with ureteral stenosis and ureteral colic
• Fornix rupture due to pressure increase in the renal pelvicocaliceal system

In acute colic, analgesic treatment is the main treatment.

Suitable agents for this purpose are:

• Metamizol: 1 g - 2 g i.v. is the drug of first choice, as it also has a spasmolytic and antinociceptive effect on the ureter.
• Paracetamol: 1 g i. v.
• Diclofenac: 75 mg / kg bw i. v.
• Morphine: 0.1 mg / kg bw i. v.

In a randomized study, the combination of paracetamol and diclofenac was shown to be superior to the administration of morphine for pain relief (Seitz 2018).

The solubility of cystine - assuming a physiological pH 4.5 - 7.0 of the urine - is about 300 mg / d (Kasper 2015). Therefore, there are several therapeutic options:

• 1. to reduce the concentration of cystine in the urine, the patient should always drink high amounts of ≥ 3.5 l / d evenly distributed over 24 h. In infants, this may include, among other things, the use of a high volume of water. In infants, this may require the insertion of a PEG tube(Seitz 2018).
• 2. a methionine-reduced diet (protein-reduced diet with < 100 g protein / d [Müller 2007]) is recommended to reduce cystine excretion, since methionine is metabolized to cystine in the body (Weigert 2018).
• 3. to improve the solubility of cystine are possible:
  • 3a. Alkalinization of the urine to a pH value significantly > 7.5 with e.g. sodium bicarbonate. The dose depends on the urine pH, which should initially be measured several times a day. As a rule, the dosage is between 40 mmol - 80 mmol / d. The solubility of cystine is tripled by the alkalinization of urine (Kuhlmann 2015).
  • 3b. ACE- inhibitors (such as captopril, enalapril). The latter lead to the formation of thiolcysteine disulfide and thus to better solubility of cystine. Cystine excretion can thus be reduced by about 50% (Kuhlmann 2015).
• 4. if the above measures are not sufficient or there is already a very high excretion of cystine initially, treatment to bind cystine in the urine with the following drugs is recommended in addition to the above measures (Seitz 2018):
  • 4a: D- Penicillamine, which forms soluble heterodimers together with cystine. With D- penicillamine, significant side effects in the form of exanthema, fever, nephrotic syndrome, etc. can occur - especially in high doses and with rapid up-dosing (Dötsch 2017). To mitigate these, a slow dose increase over several weeks is recommended (Kuhlmann 2015). Under D-penicillamine treatment, there is a decrease in vitamin B 6 serum levels, which is why pyridoxine should be regularly substituted with high doses(Weigert 2018). Dosage recommendation in cystinuria: up to 600 mg / d orally (absorption is 70%) [Hoffmann 2004].
  • 4b: Tiopronin

Tiopronin has significantly fewer side effects than D-penicillamine. Dosage recommendation: e.g. Captimer 7 - 10 mg / kg bw / d, distributed over 3 - 4 single doses (Dötsch 2017).

• Ascorbic acid: Ascorbic acid can reduce cystine to cysteine. However, since so far the effectiveness is not exactly clarified, the therapeutic use is difficult.

Furthermore, vitamin C degradation can lead to increased endogenous oxalate production (Weigert 2018) and thus to hyperoxaluria with the risk of calcium nephrolithiasis (see also types of urinary stones) (Kuhlmann 2015).

• Extracorporeal shock wave lithotripsy (ESWL):

Cystine stones are not suitable for extracorporeal shock wave lithotripsy due to their hard consistency (Manski 2019).

Further therapeutic measures such as

• Urinary diversion
• Stone removal by
  • endurological interventions
  • percutaneous nephrolithotomy (PCNL)
  • laparoscopic or open procedures

s. Nephrolithiasis.

The prognosis of cystinuria is usually favorable with appropriate therapy and compliance of the patient. Occasionally, however, there are courses of the disease that do not respond to therapeutic measures. In these cases, chronic kidney damage may result, including kidney failure requiring dialysis (see dialysis procedures).

(Kuhlmann 2015)

Terminal renal failure can also occur in ignorance of the diagnosis, especially after:

• unilateral nephrectomy
• Frequent surgical procedures (Weigert 2018).

Patients are cured of cystinuria by renal transplantation(Kuhlmann 2015).

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