Aminoaciduria and cystinuria

Aminoaciduria (amino acid) is an increase in the excretion of amino acids in the urine or the presence of amino acids in the urine that are not normally contained in it (for example, ketone bodies).

[1], [2], [3], [4], [5]

Causes of the aminoaciduria and cystinuria

Reabsorption of most amino acids is carried out by the epithelial cells of the proximal tubules, which have 5 main transporters on the apical membrane. In addition, for some amino acids there are also specific vectors.

Renal aminoaciduria develop with genetically determined or, more rarely, acquired dysfunction of the corresponding tubular transporter.

The non-cardiac aminoaciduria is caused by a persistent increase in the content of the corresponding amino acid in the blood, which is most often observed with hereditary deficiency of enzymes that ensure its metabolism and / or excessive formation of it.

[6], [7], [8], [9], [10]

Symptoms of the aminoaciduria and cystinuria

Aminociduria with excretion of cystine or dibasic amino acids

Cystinuria is combined with an increase in the excretion of dibasic amino acids or exists in isolation. There are three types of cystinuria.

Variants of cystinuria
 

A type	Features	Manifestations
I II III	Combined with the absence of intestinal absorption of cystine and dibasic amino acids Combined with the absence of intestinal absorption of cystine, but not dibasic amino acids Intestinal absorption of cystine and dibasic amino acids decreased	Cystinuria only in homozygotes; in the heterozygous aminoaciduria is not present Aminoaciduria in homo- and heterozygotes; in the latter, its expression is less Aminoaciduria in both homo- and heterozygotes

"Classic" cystinuria is a disease inherited by an autosomal recessive type and, as a rule, combined with a violation of absorption of this amino acid in the intestine. The clinical significance of insufficient absorption of cystine in the intestine is small.

Isolated hypercystinuria, not combined with an increase in the excretion of dibasic amino acids, is observed extremely rarely. As a rule, in these patients the family history is not burdened.

The clinical symptoms of cystinuria depend on the intensity of nephrolithiasis. In patients with cystinuria, renal colic,  hematuria, a tendency to urinary tract infections are observed  . Obstruction of the ureter occurs infrequently, mainly in men. With the bilateral nature of cystine nephrolithiasis, kidney failure sometimes develops.

Two types of isolated dibasic aminoaciduria without cystinuria are described. Type 1 is characterized by increased excretion of arginine, lysine and ornithine. The disease is inherited by autosomal recessive type, renal tubular dysfunction is combined with impaired absorption of dibasic amino acids in the intestine. The consumption of large amounts of protein by patients with this disease leads to an increase in the content of ammonium ions in the blood and severe alkalosis, accompanied by vomiting, weakness, and consciousness disturbance.

With isolated dibasic aminoaciduria of type 2, the excretion of arginine, lysine and ornithine is also increased, but episodes of hyperammonemia are not observed.

Isolated lisinuria is rarely diagnosed. This version of tubular dysfunction is always combined with mental retardation.

Aminoaciduria with excretion of neutral amino acids is represented  by Hartnup disease  and histidineuria. Clinical symptoms of aminoaciduria depend on the form of the disease.

Hartnup disease is named after the family name of the English family, in which this disease was first described. At the heart of Hartnup disease lies the insufficiency of the tubular transporter of neutral amino acids. Reabsorbed less than half of the filtered alanine, asparagine, glutamine, isoleucine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine and valine. The reabsorption of histidine is completely impaired. Absorption of neutral amino acids in the intestine in Hartnup's disease is also impaired.

Symptoms of Hartnup's disease are mainly due to the symptoms associated with the deficiency of nicotinamide, which is formed mainly from tryptophan. Typical are photodermatitis (such as pellagra), cerebellar ataxia, emotional lability, and sometimes mental retardation.

Single observations of isolated histidineuria are described. All patients were diagnosed with a violation of absorption of this amino acid in the intestine and mental retardation.

Iminoglycinuria and glycinuria

Iminoglycinuria is an autosomal recessive tubular dysfunction characterized by an increase in the excretion of proline, hydroxyproline, and glycine. As a rule, it is asymptomatic.

Isolated glycinuria is also a benign condition, apparently inherited in an autosomal dominant type. Occasionally, nephrolithiasis is observed.

[11], [12], [13]

Aminoaciduria with excretion of dicarboxylic amino acids

Increase in the excretion of dicarboxylic amino acids (aspartic and glutamine) is extremely rare, it is asymptomatic. Combinations of this tubular dysfunction with hypothyroidism and mental retardation are described, but their relationship is not established.

[14], [15], [16], [17], [18]

Forms

Aminoaciduria is divided into renal and non-renal.

Renal aminoaciduria 

Disruption of amino acid transport	Diseases
Cystine and dibasic amino acids	"Classic" cystinuria Isolated hypercystinuria Dibasic aminoaciduria - type 1 - type 2 Lysinuria
Neutral amino acids	Hartnup disease Histidineuria
Glycine and iminoacids	Iminoglycinuria Glycinuria
Dicarboxylic amino acids	Dicarboxylic aminoaciduria

[19], [20], [21], [22]

Diagnostics of the aminoaciduria and cystinuria

Laboratory diagnostics of cystinuria

The diagnosis of cystinuria is confirmed by the discovery of cystine crystals in the urine. A qualitative colorimetric cyanide-nitroprusside test is used for screening.

The diagnosis of Hartnup's disease is confirmed by the study of the content of neutral amino acids in the urine by chromatography.

[23], [24], [25], [26], [27], [28]

Treatment of the aminoaciduria and cystinuria

Treatment of cystinuria involves a decrease in the concentration of cystine in the urine and an increase in its solubility. Recommend constant alkalinization of urine (the target pH> 7.5) and the intake of a large amount of liquid (4-10 l / day).

The expediency of using penicillamine in cystinuria is due to its ability to form a well-soluble disulfide complex with cystine. Penicillamine is prescribed in a dosage of 30 mg / kghsut), in adults, if necessary, the dosage is increased to 2 g / day. In patients taking penicillamine, it is necessary to monitor the excretion of proteins in the urine in connection with the risk of developing membranous nephropathy with nephrotic syndrome.

Patients with cystinuria showed a restriction of consumption of table salt. In the development of cystine nephrolithiasis, conventional surgical methods of treatment are used.

Patients with isolated dibasic aminoaciduria without cystinuria are recommended to follow a diet with a reduced protein content.

For the treatment of Hartnup's disease, nicotinamide is prescribed.