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

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X-linked recessive nephrolithiasis is an X-linked disorder affecting proximal tubular reabsorption. To know more about it, read the following article.

Published At September 26, 2022
Reviewed AtApril 26, 2023

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.

Frequently Asked Questions

1.

What Is the Ideal Method of Treating Kidney Stones?

The treatment varies depending on the type, size, and cause of the kidney stone. The smaller kidney stones do not require invasive treatment, whereas the larger stones that cause symptoms may require surgery or sound waves to break up the rocks. The best treatment for kidney stones is:
Drinking Lots of Water - Consuming up to two to three quarts (1.8 to 3.6 liters) of liquid daily can keep your urine diluted and help prevent the development of kidney stones.

2.

Which Genetic Conditions Result in Kidney Stones?

Kidney stone risk can rise due to genetic alterations, which frequently occur due to several environmental and lifestyle factors. Most genes in this condition are crucial for transferring chemical signals from outside cells to inside cells. Some of the rare genetic disorders that cause kidney stones are:
 - Adenine phosphoribosyltransferase (APRT) deficiency. 
 - Cystinuria.
 - Dent disease. 
 - Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC).
 - Primary hyperoxaluria (PH).

3.

What Naturally Removes Kidney Stones?

One of the primary keys to removing kidney stones is to stay hydrated. It is a crucial component in passing kidney stones and avoiding the formation of new ones by drinking plenty of fluids. The fluid not only helps transport stones and other foreign matters through your urinary tract, but it also flushes away the toxins. Although water might be sufficient to recover from this condition, adding some natural ingredients might be even more beneficial. Before starting with any home remedies, it is better to consult a doctor so they can determine whether these methods are appropriate for you or if they could have other adverse effects. After consuming any natural remedy, immediately drink one (8-ounce) glass of water. This helps carry the raw ingredients through your body. Some natural ingredients used to remove kidney stones include lemon juice, apple cider vinegar, celery juice, basil juice, pomegranate juice, and kidney bean broth.

4.

What Foods Should Someone With Nephrocalcinosis Avoid?

It is a condition where too much calcium gets deposited in the kidneys. One must avoid the following foods to reduce the amount of calcium oxalate stones passed in the urine and to use the right amount of calcium in the diet. The following foods to be avoided are:
 - Avoid consuming too much protein foods.
 - Avoid consuming too much salt.
 - Avoid consuming vitamin C foods and supplements.
 - Avoid consuming oxalate-rich foods like peanuts, spinach, sweet potatoes, nuts, and rhubarb.

5.

What Should You Avoid Drinking When You Have Kidney Stones?

People with kidney stones should avoid consuming carbonated drinks like cola, which has a high content of phosphates and other chemicals which helps form kidney stones. Furthermore, these beverages contain higher amounts of sugar syrups like sucrose and fructose, which elevate the risk of kidney stone formation and exacerbate pre-existing kidney stones.

6.

How Can I Reduce the Calcification in My Kidneys?

Since calcifications result from different biological processes, there is no proven way to prevent them. Depending on where the accumulation is, quitting smoking and making dietary changes may affect the development of calcifications. Certain diet restrictions may reduce the frequency of kidney stone formation. However, it is necessary to prevent it from becoming a more severe condition, ensure enough fluid intake, and treat the underlying cause. Surgical therapy may be suggested in more severe cases of stone formation in the renal tract, mainly if the stone results in obstruction and recurring infections.

7.

Does Removing Kidney Stones Improve Kidney Function?

Most persons who have symptomatic kidney stones pass them on their own. Treatments like shock wave lithotripsy (SWL) and ureteroscopy are the two most frequent ways to remove stones for those unable to do it. Patients with large rocks, those who failed to do the above treatments, and those with specific renal and ureteral anatomic anomalies are treated with percutaneous nephrolithotomy (PCNL). Some patients might need open, robot-assisted, or laparoscopic surgery to remove stones. Renal dysfunction occurs when a stone blocks the kidney, which usually improves or goes away when the stone is removed. However, depending on the stone removal techniques, it could harm renal function directly or indirectly.

8.

Does Kidney Stones Get Triggered by Stress?

Yes, stress can cause kidney stones to form, particularly when accompanied by long-term dehydration. This is because the kidneys can suffer from generalized anxiety. Moreover, stress can contribute to elevated blood pressure and blood sugar levels, adversely affecting the kidneys and the heart, thereby triggering the formation of kidney stones.

9.

Is Kidney Stone Surgery Serious?

There are various types of kidney stone surgery present. They are percutaneous nephrolithotomy and nephrolithotripsy, ureteroscopy, shockwave lithotripsy, and open surgery. Significant issues like severe bleeding or damage to the kidney and surrounding structures are rare. The most frequent problems include pain at the location of the small incision, the requirement for a stent or tube to facilitate kidney drainage temporarily, and blood in the urine is common.

10.

Does Dehydration Cause Kidney Stones?

Insufficient hydration can also contribute to developing kidney stones and urinary tract infections, which can lead to significant complications if not adequately addressed. When enough water stops the stone-forming crystals from joining together, kidney stones are less likely to form. In addition, the stone formation has been directly linked to a lack of fluid consumption. Low fluid intake reduces diuresis, which causes urine to become concentrated. Thus kidney stones may develop as a result of the minerals becoming oversaturated.

11.

Does Kidney Stones Affect You Mentally?

Many studies have found that stone episodes and the resulting medical or surgical care impact a patient's physical, emotional, and psychological well-being. Urolithiasis has been linked to anxiety, depression, and low quality of life.

12.

Does Probiotics Help in Treating Kidney Stones?

Kidney stones might develop when the amount of dissolved substances in the urine, such as oxalate, calcium, and uric acid, is more significant than what would usually be dissolved. Multiple studies have indicated the potential benefits of probiotic bacteria, including Oxalobacter formigenes, Lactobacillus, and Bifidobacterium, in reducing urine oxalate levels. These beneficial bacteria may accomplish this by breaking down dietary oxalate in the gastrointestinal tract, enabling its absorption.
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Dr. Samer Sameer Juma Ali Altawil
Dr. Samer Sameer Juma Ali Altawil

Urology

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