Urolithiasis, Cystine

Basics

Overview

Formation of uroliths, composed of cystine in the urinary tract.
Occurs with cystinuria, an inborn error of metabolism caused by defective tubular reabsorption of cystine, ornithine, lysine, and arginine (COLA) leading to cystine urolith formation.
Cystine is freely filtered by glomeruli; most is actively reabsorbed in the proximal tubules.
Impaired intestinal absorption of these amino acids has not been associated with any nutritional deficiency states in dogs, presumably because they are non-essential amino acids.
Unless protein intake is severely restricted, cystinuric dogs have no detectable abnormalities associated with amino acid loss. Excessive loss of arginine in urine predisposes cats to hyperammonemic encephalopathy. Some cystinuric dogs may have carnitinuria.
Cystinuric dogs have been classified into three different types: Type 1 autosomal recessive SLC3A1 mutations found in Newfoundlands, Landseer, and Labrador retrievers; Type 2 autosomal dominant SLC7A9 identified in Australian cattle dogs and European Miniature Pinschers, and Type 3, which has sex limited inheritance and has been identified in Mastiff and related breeds, Scottish Deerhound, and Irish Terriers.
Because not all cystinuric dogs and cats form uroliths, cystinuria is a predisposing rather than a primary cause of cystine urolithiasis. Cystine is relatively insoluble in acid urine; becomes more soluble in alkaline urine.
A genetic missense mutation of the SLC3A1 Gene has recently been identified in one cat with cystine uroliths.

Signalment

Dogs-primarily adult (mean age 5 years; range 3 months–14 years) males but may also affect females. It occurs in excess of 80 breeds, including dachshunds, English bulldogs, Newfoundlands, Labrador retrievers, Chihuahuas, pit bulls, and French bulldogs. May be detected in male and female Newfoundland and Labradors <1 year of age.
Cats-primarily adult (mean age at diagnosis, 3.5 years; range, 4 months–12 years) males and females; most common the domestic shorthair and Siamese breeds.

Signs

Depend on location, size, and number of uroliths; affected animals may be asymptomatic.
Urocystoliths-include pollakiuria, dysuria, and hematuria.
Urethroliths-include pollakiuria, dysuria, and sometimes voiding of small smooth uroliths. Complete outflow obstruction may result in post-renal azotemia that may progress to uremia.
Nephroliths-typically asymptomatic; may be associated with manifestations of hydronephrosis and renal insufficiency.

Causes & Risk Factors

Cystinuria is a risk factor.
Breed predisposition.
In young and middle-aged dogs with previous history of cystine urolithiasis-recurrence within 6–12 months following surgery unless prophylactic therapy is given.
Urolith formation-enhanced by acidic, concentrated urine, incomplete and infrequent micturition.

Diagnosis ⬆ ⬇

Diagnosis

Differential Diagnosis

Uroliths mimic other causes of pollakiuria, dysuria, hematuria, and/or outflow obstruction.
Differentiate from other types of uroliths by urinalysis, radiography, and quantitative analysis of voided or retrieved uroliths.

CBC/Biochemistry/Urinalysis

Cystine crystals are six-sided; insoluble in acetic acid.
Positive urine cyanide- nitroprusside test.

Other Laboratory Tests

Urinary amino acid profiles-reveal abnormal quantities of cystine and, in some dogs and cats, ornithine, lysine, arginine, and other amino acids.
Quantitative mineral analysis of uroliths.
DNA test.

Imaging

Radiography-the radiodensity of cystine uroliths is similar to that of struvite and silica, less than that of calcium oxalate and calcium phosphate, and greater than that of ammonium urate; when large enough, cystine uroliths can be detected by survey radiography.
Ultrasonography-can detect cystine uroliths; does not provide reliable information about the radiodensity or shape.

Diagnostic Procedures

Urethrocystoscopy-used to detect cystine urethroliths and urocystoliths.

Treatment ⬆ ⬇

Treatment

In dogs: Medical dissolution of uroliths by a combination of N-(2-mercaptopropionyl)-glycine (2-MPG) and dietary therapy; Hill's Prescription Diet Canine u/d reduces urinary excretion of cystine, promotes formation of alkaline urine, and reduces urine concentration; it is used in conjunction with 2-MPG for urolith dissolution and is often effective alone in preventing recurrence of cystine uroliths.
In one study, castration reduced recurrence of cystine uroliths in dogs identified with Type 3, sex limited inheritance.
In cats: Diets designed for renal insufficiency and geriatric cats may be suitable to minimize formation. Give enough potassium citrate (40–75 mg/kg PO q12h) to maintain a urine pH of 7.5. Choose a moist formulation diet to help reduce urine concentration. Dissolution with 2-MPG has been studied in a small number of cats at an oral dose of 12–20 mg/kg q12h. Frequency of recurrence was minimized in these cats without adverse side effects.
In dogs, and cats, remove urocystoliths unable to be dissolved by voiding urohydropropulsion, basket retrieval, lithotripsy, or surgery.

Medications ⬆ ⬇

Medications

Drug(s)

Urine Alkalinizers

For patients that have acidic urine despite dietary therapy and control of urease-positive urinary tract infections.
Data from cystinuric humans suggest that dietary sodium may enhance cystinuria; thus potassium citrate may be preferable to sodium bicarbonate as a urine alkalinizer. Give enough potassium citrate (40–75 mg/kg PO q12h) to maintain a urine pH of 7.5.

Thiol-Containing Drugs

2-MPG decreases urine concentration of cystine by combining with cysteine to form cysteine-2-MPG, which is more soluble than cystine.
With status as an orphan drug, Thiola™ is only available from the distributor Retrophin. Generic 2-MPG (Tiopronin) may be obtained from compounding pharmacies. In dogs: 2-MPG may be given at a dosage of 15–20 mg/kg PO q12h to dissolve canine cystine uroliths in conjunction with dietary therapy. In our hospital, mean dissolution time was 78 days (range, 11–211 days).
2-MPG may be given at a lower dosage (5–10 mg/kg PO q12h) to prevent recurrent canine cystine uroliths.
In cats: 2-MPG has been studied in a small number of cats at an oral dose of 12–20 mg/kg q12h. Frequency of recurrence was minimized in these cats without adverse side effects.
Drug-induced adverse events associated with 2-MGP are uncommon in dogs; they include reversible Coombs'-positive spherocytic anemia, thrombocytopenia, glomerular proteinuria, myopathy, aggressiveness, and increased hepatic enzyme activity.
2-MPG should be used with caution in cats, as the efficacy and safety of 2-MPG has not been thoroughly evaluated in normal or cystinuric cats.

Follow-Up ⬆ ⬇

Follow-Up

Minimize recurrence with dietary management or 2-MPG.
Monitor urolith dissolution at 30-day intervals by urinalysis, survey or contrast radiography, or ultrasonography.
Although cystine uroliths tend to recur, recurrence does not affect all cystinuric dogs and cats.
In some older dogs, the rate of recurrence declines as a consequence of a reduction in the magnitude of cystinuria.

Miscellaneous ⬆

Miscellaneous

Abbreviation

2-MPG = N-(2-mercaptopropionyl)-glycine

Suggested Reading

Bannasch D, Henthorn PS. Changing paradigms in the diagnosis of inherited defects associated with urolithiasis. Vet Clin North Am Small Anim Pract 2009, 39:111–125.

Brons AK, Henthorn PS, Raj K, et al. SLC3A1 and SLC7A9 mutations in autosomal recessive or dominant canine cystinuria: A new classification system. J Vet Intern Med 2013, 27:1400–1408.

Mizukami K, Raj K, and Giger U. Feline Cystinuria caused by a missense mutation in the SLC3A1 gene. J Vet Intern Med 2015, 29:120–125.

Authors Carl A. Osborne, Jody P. Lulich, Eugene E. Nwaokorie, and Lisa K. Ulrich

Consulting Editor Carl A. Osborne

section name header

Basics ⬇

Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Medications ⬆ ⬇

Follow-Up ⬆ ⬇

Miscellaneous ⬆