X-Linked Recessive Nephrolithiasis - Symptoms, Causes, Diagnosis and Treatment.

Introduction

X-linked recessive nephrolithiasis is a rare genetic disorder affecting the kidney. It shows an X-linked recessive inheritance pattern affecting males exclusively. The gene mutations of this disorder are found to be sporadic, with no family history of this disorder. The symptoms may appear in childhood, or they may show up during adulthood. In some cases with gene mutations, it will not produce any symptoms, and to another extent, the symptoms may progress to end-stage renal disease. It was initially thought that the disease-causing locus in the gene for X-linked recessive nephrolithiasis is different from dent disease, and they were treated as separate entities.

What Is X-linked Recessive Nephrolithiasis?

X-linked recessive nephrolithiasis, also known as Dent disease, is a hereditary condition that shows proximal tubular reabsorption failure. Clinically characterized by the presence of proteinuria, nephrocalcinosis, hypercalciuria, kidney stones, rickets, and renal failure.

What Is the Etymology of X-linked Recessive Nephrolithiasis?

In 1964, Dent and Friedman first described this condition in two unrelated British boys with rickets and associated symptoms of X-linked recessive nephrolithiasis. Then, in 1990, the neurologist Dr. Oliver Wrong fully described this condition and named it after his mentor, Dr.Dent. Other terminologies include X-linked recessive nephrolithiasis with renal failure, X-linked recessive hypercalciuric hypophosphatemic rickets, and idiopathic low molecular weight proteinuria with hypercalciuria and nephrocalcinosis.

What Is the Etiology of X-linked Recessive Nephrolithiasis?

It is caused due to the mutation in the CLCN5 gene located on chromosome Xp11.22. It is a voltage-gated chloride transporter mutation of the CLCN5 gene that would result in the inactivation of the chloride channels, thus failure of the proximal tubules to reabsorb the micro and macro elements, and subsequently, the symptoms develop. Studies report that 15 % of cases with X-linked recessive nephrolithiasis show mutations in the OCRL1 gene (inositol polyphosphate 5-phosphatase) that encodes for phosphatase enzyme involved in actin polymerization and regulates membrane trafficking. OCRL1 gene mutations are commonly associated with Lowe syndrome; patients with mutated OCRL1 gene X-linked recessive nephrolithiasis will show the features of Lowe syndrome along with it.

What Are the Types of X-linked Recessive Nephrolithiasis?

It can be categorized into two types based on which gene mutation is causing the disease,

• Dent Disease Type 1 - If it is caused due to CLCN5 gene mutation.

• Dent Disease Type 2 - If it is caused due to OCRL 1 gene mutation.

Both types show similar symptoms, with type 2 associated with Lowe syndrome, such as mild intellectual disability, hypotonia (decreased muscle tone), cataracts, etc.

What Is the Inheritance Pattern of Dent Disease?

It shows an X-linked recessive pattern of inheritance. It shows an X-linked recessive pattern of inheritance. This is because the CCLN5 and OCRL1 genes are located on the X chromosome. The recessive pattern of inheritance usually needs the mutated gene to be present in both chromosomes to cause the disease. But in males, only one copy of the X chromosome is present in their genetic makeup. So one copy of the X chromosome carrying the mutated gene is enough to cause the disease.

What Is the Pathogenesis of X-linked Recessive Nephrolithiasis?

The mutation in the CLCN5 gene encodes for CLC-5, which is a chloride channel exchanger. This CLC-5 is mainly expressed in the kidneys, specifically in the proximal convoluted tubules. It is responsible for reabsorbing elements such as albumin and low molecular weight proteins and prevents excretion in urine. The mutations in the CLCN5 gene will affect the reabsorption effect of the proximal renal tubules leading to urinary loss of low molecular weight proteins leading to proteinuria, loss of calcium in the urine causing hypercalciuria, aggregation of calcium phosphates in the tubular lumen causing nephrocalcinosis and nephrolithiasis (kidney stones). This subsequently develops into an end-stage renal disease.

What Are the Symptoms of X-linked Recessive Nephrolithiasis?

The symptoms are mainly caused due to the disturbed reabsorption capacity of the proximal tubules, thereby leading to the loss of micro and macro elements in the urine. The symptoms include,

• Dehydration - Lose more fluid from the body.

• Polyuria - Frequent urination.

• Polydipsia - Excessive thirst.

• Proteinuria - Excessive loss of proteins in the urine.

• Nephrolithiasis - Formation of kidney stones due to the accumulation of calcium phosphate crystals in the kidneys.

• Hypercalciuria - Increased loss of calcium in the urine.

• Phosphaturia- Loss of phosphate in the urine.

• Kaliuresis - Loss of potassium in the urine.

• Aminoaciduria- Loss of amino acids in the urine.

• Rickets - Bone disease as a result of calcium loss and decreased absorption of Vitamin D.

• Nephrocalcinosis - Deposition of excessive calcium in the kidneys.

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How Is X-linked Recessive Nephrolithiasis Diagnosed?

The steps in diagnosis include,

1. History:

• A detailed history taken from the patient would help in understanding the symptoms of the disease.

2. Clinical Examination:

• A thorough clinical examination of the patient to check for the signs and symptoms of Dent's disease when it is associated with Lowe syndrome.

3. Urine Test:

• Proteinuria - Urine examination would reveal the excessive loss of low molecular weight proteins in the urine.

• Hypercalciuria - Presence of excessive calcium in the urine.

• Hyperphosphaturia - Presence of phosphate in the urine.

• Kaliuresis - Presence of potassium in the urine.

• Aminoaciduria - Presence of amino acid in the urine.

• Hematuria - Presence of blood in the urine.

4. Kidney Ultrasound:

• Would reveal the presence of renal stones (nephrolithiasis) and nephrocalcinosis (deposition of calcium phosphate salts in the kidney).

5. Microscopic Examination:

• Histopathological findings are nonspecific and are usually not needed in the diagnosis of Dent's disease. It may reveal the changes such as focal segmental glomerulosclerosis.

6. Genetic Testing:

• This provides the confirmatory diagnosis of the condition. Genetic markers are used to locate the mutated gene locus in the X chromosome.

How Is X-linked Recessive Nephrolithiasis Treated?

There is no specific treatment for X-linked recessive nephrolithiasis; treatments are aimed at relieving the symptoms and preventing the condition from progressing to renal failure. The treatment involves a team of specialists such as pediatricians, nephrologists, general physicians, dieticians, and genetic counselors.

• Thiazide Diuretics - These are reported to be effective in reducing the incidence of hypercalciuria and kaliuresis. It also prevents the development of kidney stones.

• Amiloride- It is also found to increase calcium reabsorption in the proximal tubules.

• ACE Inhibitors or ARBs- Angiotensin-converting enzyme inhibitors and Angiotensin receptor blockers are useful to reduce the incidence of proteinuria and prevent the further progression of kidney disease.

• Vitamin D - It is used to treat rickets.

• High Citrate Diet - Diet rich in citrate are reported to increase the proficiency of the kidneys and prevent kidney failure.

• Hemodialysis / Peritoneal Dialysis - It is required in patients progressing to renal failure.

• Renal Transplantation - It is indicated in patients with renal failure.

Conclusion

X-linked recessive nephrolithiasis is a rare kidney disorder with X linked recessive inheritance pattern. It comprises a group of disorders that, left untreated, progress to kidney failure. Prior counseling of the parents of children affected with the disease would help in better survival. Supportive treatments are given to control the complications.