Urine Crystals in a 1-year-old Male

Justin Fender, BS; Monte S. Willis, MD, PhD; Yuri Fedoriw, MD

Disclosures

Lab Med. 2010;41(7):388-392. 

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1. The most striking clinical findings included fever (>39°C), vomiting, and painful urination. The most striking laboratory findings included the presence of hexagonal polarizable crystals (Image 1), increased urinary ketones, and hematuria. The mild degree of hematuria is a non-specific, albeit abnormal, finding that likely represents ongoing mechanical trauma and irritation of the urinary tract epithelium by the identified crystals.

Image 1.

Crystals microscopically identified in the patient's urine sediment (x60) (left) and under polatrized light (right). Lamination of the crystal can be appreciated on a magnified view (insert, left). Cellular cases are present in the background (arrows).

Though hematuria and pyuria by dipstick testing is useful as a screening test, microscopic examination of urine sediment is important to evaluate renal disease. Small amounts of crystals, bacteria, cells, or casts may be observed in healthy individuals, but increases are indicative of a more significant underlying pathology. The formation of crystals in the urine depends upon many factors, including the degree of supersaturation of constituent molecules, the presence of crystallization inhibitors, and pH. The morphologic appearance of urinary crystals can often be the first indication of a specific pathologic process. Pleomorphic, rhombic plates, or rosettes characterize common uric acid crystals, which may be observed in acidic urine favoring the conversion of soluble urate salt into insoluble uric acid. The formation of calcium oxalate crystals, conversely, is not dependent on the urinary pH. Calcium oxalate monohydrate crystals can be either dumbbellshaped or coarse and needle-shaped, while calcium oxalate dihydrate crystals are characteristically envelope-shaped. The combination of acute renal failure and calcium oxalate crystals is often observed in ethylene glycol ingestion. The crystals of magnesium ammonium phosphate, also called struvite, and calcium-apatite are the constituents of struvite stones. Magnesium ammonium phosphate crystals have an unmistakable "coffin lid" appearance. When a urinary tract infection with urease-producing organisms occurs, such as Klebsiella or Proteus spp., ammonia production is increased and the urine pH is elevated; decreased solubility of phosphate in alkalinized urine results in stone formation. Finally, hexagonal crystals, like those seen in this case, are composed of cystine. Although such crystals are pathognomonic for increased urinary cystine, the pathophysiologic mechanism underlying cystinuria cannot be established by microscopic examination alone.

2. In a pediatric patient presenting with a fever and dysuria, many infectious and non-infectious causes may be the source of the symptoms. However, these findings usually stem from one of the common disorders of childhood.[1–3] Infectious causes include pyelonephritis, lower urinary tract infections, urethritis, and balanitis. Noninfectious causes include exposure to irritants or trauma. Other causes include urinary stones, urethral strictures, and dysfunctional elimination. It has been noted that patients with idiopathic hypercalciuria and idiopathic hyperuricosuria may complain of dysuria even in the absence of an observable renal stone.[4,5]

In infants and children, ketonuria occurs in association with a variety of conditions, including acute febrile illness and toxic states accompanied by vomiting or diarrhea. When the ketonuria is severe and persistent, inherited metabolic disease should be suspected. Other causes of ketonuria include exposure to cold or severe exercise and the use of a low-carbohydrate diet for weight reduction. Irrespective of cause, systemic ketoacidosis can often provide a warning of impending coma.

In this case, the most specific laboratory finding is identification of hexagonal polarizable crystals representing supersaturated urinary cystine. Although these crystals are not entirely specific, they raise a rather focused differential including cystinuria and Fanconi syndrome, the latter of which can be either primary (idiopathic) or secondary to many potential inborn errors of metabolism. These metabolic disorders include cystinosis, tyrosinemia type 1, fructose intolerance, Wilson disease, glycogen storage disease type 1, respiratory chain disorders, Fanconi-Bickel syndrome, and lysinuric protein intolerance. Cystinuria, an autosomal recessive metabolic disorder related to defective dibasic amino acid reabsorption, represents the most common error of amino acid transport. Irrespective of underlying etiology, the proximal tubular dysfunction of Fanconi syndrome gives rise to hyperaminoaciduria, most frequently related to increased urinary histidine, glycine, serine, alanine, glutamine, and/or cystine. Associated increases of urine glucose, phosphate, bicarbonate, potassium, calcium, uric acid, or carnitine are common. Fanconi syndrome can cause nephrolithiasis directly through prolonged hypercalciuria or iatrogenically following conservative treatment with phosphate and vitamin D.[6]

3. Most likely diagnosis: Cystinuria

As discussed above, hexagonal polarizable crystals are pathognomonic for increased urinary cystine related to either primary cystinuria or Fanconi syndrome. The latter is typically associated with proximal renal tubular dysfunction and resultant hyperaminoaciduria, leading to elevated levels of histidine, glycine, serine, alanine, and glutamine. Reportedly, subsequent 24-hour urine collection was analyzed in this patient and demonstrated increased urinary cystine, ornithine, arginine, and lysine.

Cystinosis represents the most common inherited cause of Fanconi syndrome although the incidence is exceedingly rare (1:100000 births). This autosomal recessive lysosomal storage disease is characterized by intracellular accumulation of cystine and is associated with multi-organ system dysfunction. Three distinct forms have been recognized and, as the name implies, the nephropathic form presents with progressive renal dysfunction. However, urinary crystals are not typically demonstrable, and systemic accumulation of cystine produces a pattern of symptoms and physical findings not present in this case.[7] Other causes of Fanconi syndrome can be considered in the differential diagnosis, although they are far less likely.

Conversely, cystinuria likely represents the most common genetic disorder of amino acid transport with an average incidence of 1:7000. It demonstrates an autosomal recessive inheritance pattern and is characterized by impaired renal and intestinal transport of dibasic amino acids including ornithine, arginine, lysine, and cystine. Of these, only the oxidized dimer of cystine precipitates, potentially leading to crystal and/or stone formation.[8–11] Importantly, only a fraction of patients with cystinuria form cystine crystals, owing to the complex microenvironmental and biophysical factors potentiating crystallization.

4. The characterization of the clinical manifestations of cystinuria was made before the underlying cause of the disease was known in 1966.[12] Originally, there were 3 types of disease described based on the amount of cystine excreted by the parents:[13] Type I (0–100 umol/g creatinine), Type II (990–1740 umol/g creatinine), and Type III (100–660 umol/g creatinine). This has recently been changed to Type I (OMIM 220100) and non-Type I (OMIM 600918), the latter corresponding to the previous Type II and Type III groups.[9] Mutations in SLCA1 and SLC7A9 are responsible for the defects in dibasic amino acid transport causing cystinuria (Figure 1).[14] Mutations in SLC3A1 are responsible for most cases of Type I Cystinuria, while mutations in SLC7A are responsible for most types on non-Type I (formerly Type II and Type III) cystinuria.[14] Recently, 2 new additional causes of cystinuria have been described: (1) Hypotonia-cystinuria syndrome (OMIM 606407); and (2) 2p21 deletion syndrome. In both syndromes, SLC3A1 and a second gene (PREPL) are defective. Patients with hypotonia-cystinuria have poor muscle tone and feeding during infancy in addition to cystinuria, while patients with 2p21 deletion syndrome have an additional developmental retardation and elevated serum lactate.[15]

Figure 1.

Molecular basis of cystinuria. The SLC3A1 gene encodes the glycoprotein rBAT forming a heterodimer with the gene product of SLC7A9 (B0, +AT1), which forms the transporter of dibasic amino acids, including cystine, in the apical membrane of the proximal tubule and small intestine. Mutations in SLC3A1 (rBAT) are responsible for most cases of Type I cystinuria. Mutations in SLC7A9 are responsible for much of the non-Type I cystinuria. Recently, 2 new additional causes of cystinuria have been described where defects included a loss of SLC3A1 (see text for details).

The SLC3A1 gene encodes the glycoprotein rBAT, which forms a heterodimer with the gene product of SLC7A9. This heterodimer forms the transporter of dibasic amino acids, including cystine, in the apical membrane of the proximal tubule and small intestine (Figure 1). Defects in SLC3A1, underlying most type I cystinuria patients, results in abnormalities in how the heterodimer folds or is trafficked within the cell.[16,17] Most patients with type I cystinuria have mutations in both copies of the SLC3A1 gene; more than 100 mutations have been identified in patients with cystinuria.[18,19] The SLC7A9 gene encodes the B0, +AT1 protein, containing the subunit transporting the dibasic amino acids in the heteromeric complex.[13,20–23] Most patients with type II and type III cystinuria have defects in SLC7A9, although some carriers of SLC7A9 mutations display a type 1 phenotype.[9,24–26] Despite the extensive characterization of these 2 phenotypes related to mutations in SLC3A1 and SLC7A9, they do not explain all cases of cystinuria. In a study of 21 cystinuric children from 16 families, detailed genetic analysis identified mutations in these 2 genes in ≈70% of the patients.[27] In another study of 164 programs from the international cystinuria consortium,[18] mutations in SLC3A1 and SLC7A9 accounted for more of the patients. Of the 37 Type I patients, 90% had a SLC3A1 mutation, while 95% of the non-Type I proband had SLC7A9 mutations.[18] Mixed-type probands carried mutations in either SLC7A9 or SLC3A1, with SLC7A9 being the most represented.[18] Large rearrangements of SLC3A1 and deletions of exons 2–4 and 5–6 and duplications of exons 8–9 have been identified.[28] Complete deletion of SLC7A9 has also been identified.[28]

The original classification system was defined by the quantification of urinary amino acids in heterozygous individuals. However, with the discovery of additional responsible genes and associated mutations, classification by urinary amino acid profile has been questioned.[9] Thus, a complete categorization in this case would require genetic testing of both the patient and family. The correlation of genotype with phenotype is not entirely clear, as some mutations do not relate to crystal/stone formation or response to treatments. Referral for further genetic testing was made for this family.

5. Renal crystal and stone formation is dependent on characteristics of both solute and solvent. The solubility limit of cystine is estimated to be approximately 1 mM. Below this threshold, cystine crystals will remain dissolved in solution. However, increasing concentrations effectively supersaturate this system, predisposing to cystine precipitation and stone formation.[29] Additionally, the solubility of cystine increases proportionally to urinary pH.[29,30] Therapeutic management, therefore, is focused on maintaining an adequately low cystine concentration and alkalinizing the urine to prevent precipitation. Daily potassium citrate or potassium bicarbonate is prescribed to maintain urine alkalinity.[31] Acetazolamide has also proven effective to this end.[32,33] Some studies have identified that restricting sodium and protein may reduce cystine excretion,[34,35] partly by reducing the intake of methionine, a cysteine precursor.[35] If attempts to increase cystine solubility fail, cystine chelators are available in addition to these more conservative measures.[11,37] Penicillamine D can bind cystine to form a disulfide that is tp to 50 times more soluble than cystine alone.[11,37] The use of Tiopronin (2-mercaptopropionylglycine) works in a similar manner, but with fewer of the penicillamine D associated side effects, such as rash, fever, arthritis, leukopenia, and proteinuria.[38–40] The response to therapy can be monitored by following 24-hour urine collections to assess for volume, pH, creatinine, sodium, calcium, and crystal formation. Monitoring free cystine levels in urine has also been reported.[41] In severe cases in which stone formation has occurred, surgical options may be necessary including percutaneous nephrolithotomy with ultrasound or laser lithotripsy and renal transplantation.[42–44]

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