What is Autosomal Dominant Tubulointerstitial Kidney Disease?
Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) is a type of inherited kidney disease. This disease often progresses over time and typically results in kidney damage and a harmless substances in the urine. There’ve been many names suggested for this group of disorders over the years, including ‘Familial Juvenile Hyperuricemic Nephropathy (FJHN),’ ‘Medullary Cystic Kidney Disease (MCKD) type 2,’ and ‘Uromodulin-Associated Kidney Disease (UAKD).’ Due to these numerous names and the fact that cysts aren’t always the hallmark, it can get quite confusing. Thus, Kidney Disease: Improving Global Outcomes (KDIGO) recommends simplifying the names of these conditions to ‘Autosomal Dominant Tubulointerstitial Kidney Disease’ or ADTKD, with an additional categorization based on the specific gene involved. This is expected to bring consistency to the description of these diseases with similar genes.
ADTKD is passed down through families. Up till now, several genetic changes have been found to cause ADTKD, such as mutations in the UMOD, REN, MUC1, HNF1B, and SEC. 61A1 genes. These genes produce different proteins vital for healthy kidney functionality. The symptoms can vary and are somewhat generic, depending largely on which gene alteration is involved. Diseases resulting from changes in MUC1, UMOD, and REN genes usually only affect the kidneys. However, HNF1B gene changes can cause symptoms in other body parts too.
This disease is often difficult to identify since it is a relatively new and rare disorder that is not broadly recognized by regular healthcare providers and kidney specialists.
What Causes Autosomal Dominant Tubulointerstitial Kidney Disease?
Autosomal dominant tubulointerstitial kidney disease is a rare kidney condition caused by various mutations in different genes. There are at least five different gene mutations that cause this group of disorders. This disease is passed down through families, meaning it has what’s called an autosomal dominant inheritance pattern.
The affected genes include the MUC1 gene, which makes a protein called mucin-1, the UMOD gene, which makes a protein formerly known as Tamm-Horsfall protein but now called uromodulin, the HNF1B gene which makes a protein called hepatocyte nuclear factor 1 beta, the REN gene which makes a protein called renin, and the SEC61A1 gene which makes a protein known as translocon subunit SEC61A.
Further details on how these genetic mutations lead to the disease will be covered in the pathophysiology, or the study of how the disease develops, section of this article.
Risk Factors and Frequency for Autosomal Dominant Tubulointerstitial Kidney Disease
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare condition that isn’t fully understood yet, and we don’t know exactly how many people it affects. This disorder can impact anyone, regardless of gender, because it’s inherited in a specific way that doesn’t favor one sex over the other. If a parent has it, their child, whether a boy or a girl, has a 50% chance of getting it too. This condition can lead to severe kidney disease (known as end-stage renal disease or ESRD) typically around the age of 45, but it can happen any time between ages 17 to 75.
- ADTKD-UMOD often shows up in teenagers with symptoms like gout; many with this subtype have high uric acid in the blood.
- People living with ADTKD-REN could have symptoms such as high potassium levels, anemia, and chronic kidney disease (CKD) from a very young age.
- Those with ADTKD-MUC1 usually start getting CKD in their early twenties.
- ADTKD-HNF1B might show up as abnormalities in the urinary system in childhood, gout or diabetes in the teen years, and CKD in the third decade of life. Other abnormalities outside of the kidneys are also possible.
No matter the subtype of ADTKD, it often leads to ESRD, usually between the ages of 25 and 70. Additionally, coping with gout tends to start somewhere between the ages of 3 and 51.
While it’s a rare condition, ADTKD is thought to be one of the more common genetic kidney diseases. It’s often the cause of about 5% of all cases of CKD that are because of a single gene. The different types of ADTKD are not equally common, with ADTKD-UMOD and ADTKD-MUC1 generally seen more often than forms resulting from mutations in HNF1B or REN. In fact, many studies found that, aside from ADPKD, ADTKD-UMOD is the most frequent genetic kidney disease, affecting about 9 per million people.
Signs and Symptoms of Autosomal Dominant Tubulointerstitial Kidney Disease
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a group of inherited kidney disorders resulting from different gene mutations. They all share the same type of findings when examining kidney tissue. Although they can look similar, especially in young people, ADTKD is distinct from other kidney disorders due to its pattern of inheritance. The rate at which the kidneys lose function can vary greatly among the different types of ADTKD. Often, there are no abnormal findings in the urine, though occasionally there might be a small amount of blood. It’s rare to have protein in the urine or for the filtering units of the kidney to be involved. As the disease progresses, the kidney size may decrease and blood pressure may increase slightly.
The symptoms of ADTKD highly depend on the gene affected. Here are some examples related to specific genes:
- ADTKD-MUC1: This variant, previously known as medullary cystic kidney disease type 1, results in progressive kidney damage which can lead to end-stage kidney disease (ESRD). Individuals affected usually develop ESRD as adults, but it can occur as early as 20 and as late as 70. There are no other systemic symptoms with this form.
- ADTKD-UMOD: Historically known by several names including familial juvenile hyperuricemic nephropathy type 1 and medullary cystic kidney disease type 2, this type typically presents in teens and progresses to ESRD by middle age. Gout and high levels of uric acid are common in these patients.
- ADTKD-REN: Previously referred to as familial juvenile hyperuricemic nephropathy type 2, this variant is characterized by anemia, hyperuricemia, and symptoms of chronic kidney disease starting in childhood or adolescence. Individuals affected typically develop ESRD between the ages of 40 and 60.
- ADTKD-SEC61A1: This recently discovered variant is known to cause kidney abnormalities, anemia, and slow growth before birth. In some cases, it has also been connected with chronic kidney disease.
- ADTKD-HNF1B: This variant is caused by a mutation in the TCF2 gene and can lead to a wide range of kidney and non-kidney symptoms. These can include diabetes, abnormal liver function, birth defects of the urinary tract, and gout. Symptoms typically appear during adolescence or adulthood and often involve the development of numerous kidney cysts or underdeveloped kidneys.
Testing for Autosomal Dominant Tubulointerstitial Kidney Disease
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare and often unpredictable condition. It is important for doctors to consider this disease if a patient shows signs of kidney failure from an early age and has family members with significant kidney disease. Despite the disease’s complexity, kidney specialists can diagnose and improve patient care using specific guidelines.
Criteria to Suspect ADTKD Include:
– Having a family history that matches the typical inheritance pattern of chronic kidney disease (CKD) along with the patient’s symptoms.
– If there’s no family history of CKD but the patient has relevant kidney biopsy results, signs of an HNF1B gene mutation, or history of high uric acid levels with or without gout can also lead to suspicion of ADTKD.
Criteria to Confirm ADTKD Include:
– Family history that aligns with the inheritance pattern of CKD, relevant kidney biopsy results in a family member. (Note: You can’t confirm the diagnosis using only a kidney biopsy).
– Or, identification of mutations in specific genes in the patient or a family member.
The rate at which kidney function declines in ADTKD varies greatly, with the average age for reaching end-stage kidney disease being around 45. However, the patient could reach this stage anywhere from 17 to 75 years.
Testing for genetic changes that cause ADTKD can be complicated. For instance, testing for changes in the MUC1 gene is not a direct process and isn’t readily available at most labs. However, promising research was done recently to detect a specific MUC1 protein, though this test is also not commercially available yet.
A diagnosis of ADTKD-UMOD can be based on a patient’s symptoms combined with knowledge that a family member has a UMOD gene mutation. Genetic testing for this mutation is widely available.
For ADTKD-REN, the diagnosis should always be made through genetic testing. Measurements of renin and aldosterone hormone levels are typically inadequate because they tend to be in the low normal range in these patients.
ADTKD-HNF1B presents a wide range of symptoms, including varying kidney and other body symptoms. Luckily, cost-effective Next-Generation Sequencing (NGS) allows for rapid and simultaneous analysis of several genes, which includes HNF1B.
For ADTKD-SEC61A1, very few families have been diagnosed. This means that diagnostic criteria are still being developed.
Treatment Options for Autosomal Dominant Tubulointerstitial Kidney Disease
The treatment for autosomal dominant tubulointerstitial kidney disease primarily involves managing symptoms and slowing the progression to severe kidney disease. It’s advisable that potential family members affected by this condition manage other health risk factors, like high blood pressure, diabetes, smoking, and obesity. Regular kidney function tests are also crucial.
Currently, there aren’t many treatment choices available for children at risk for certain types of kidney diseases. However, early treatment can potentially help those with certain other conditions. Generally, individuals afflicted by this disease should be treated based on established kidney disease guidelines. Here are some treatments for specific types of the disease:
1. For ADTKD-UMOD: Allopurinol or febuxostat are mainly used to treat gout and high levels of uric acid in the blood. It’s suggested that patients take these medications as soon as gout develops to avert future gout attacks. Allopurinol, if taken early in life, could prevent gout, but it does have significant side effects and can cause severe allergic reactions. Women who may become pregnant need to be aware that this medication could cause birth defects and should stop taking it prior to pregnancy. Despite this, patients with this condition often make good candidates for kidney transplants thanks to the slow progression of kidney disease and its specificity to the kidneys alone.
2. For ADTKD-MUC1: Since there is no specific therapy yet, the best available treatment is optimal therapy for managing chronic kidney disease, such as controlling blood pressure. These patients also could be good candidates for a kidney transplant due to the slow progression of the disease.
3. For ADTKD-REN: Different treatments are available for these patients, who often have slightly low blood volume and low renin. These conditions can get worse with a low sodium diet, thus it’s important to avoid it. Hypotension and high potassium levels can be treated with a medicine called fludrocortisone or a higher salt diet.
4. For ADTKD-HNF1B: There’s no specific therapy for this condition; the treatment mainly supports managing chronic kidney disease. Medications like Allopurinol or febuxostat can be used to prevent the development of gout. Regular screenings for any liver function anomalies, high blood sugar levels, low magnesium levels, and high levels of uric acid are also part of the overall wellness management.
5. For ADTKD-SEC61A1: Even though there’s no specific therapy to treat the root cause of this condition, managing the associated congenital anemia and preventing infections can help improve the prognosis of the patient’s health.
Lastly, it’s crucial to note that some patients with ADTKD are very good candidates for kidney transplantation, especially when there are no manifestations occurring outside of the kidneys.
What else can Autosomal Dominant Tubulointerstitial Kidney Disease be?
Autosomal dominant tubulointerstitial kidney disease is a type of kidney disease that people are born with. When someone has this disease, their kidneys eventually stop working efficiently. This disease is passed down in families in a pattern known as autosomal dominant inheritance. Before diagnosing this disease, doctors must rule out other types of kidney diseases that someone may be born with. The following are some of the conditions that should be considered:
- Early-onset autosomal dominant polycystic kidney disease (another type of inherited kidney disease)
- Autosomal recessive polycystic kidney disease (a type of kidney disease inherited in a different pattern)
- Urinary tract obstruction (when something blocks the urinary tract)
- Renal dysplasia (a condition where the kidneys do not develop correctly)
- Gout (a type of arthritis that can cause kidney problems)
What to expect with Autosomal Dominant Tubulointerstitial Kidney Disease
Autosomal dominant tubulointerstitial kidney disease is often seen as a mild condition, but most patients ultimately end up with a serious condition known as end-stage renal disease. To improve the patients’ outcome, treatments should aim at delaying the progression to this severe kidney disease. The age at which the end-stage renal disease develops can differ significantly. It can happen at an early age, even during teenage years, or much later in adulthood.
While lifelong treatment can help manage the symptoms associated with chronic kidney disease, it doesn’t cure the root cause of the disease itself. Kidney transplantation has been shown to have a promising outcome, especially if the kidney is the only organ that’s affected.
Possible Complications When Diagnosed with Autosomal Dominant Tubulointerstitial Kidney Disease
End-Stage Renal Disease (ESRD) is a severe complication often seen with a genetic kidney disease known as autosomal dominant tubulointerstitial kidney disease. ESRD can cause a variety of health problems that need to be correctly identified and treated. Here are some common complications tied to ESRD:
- Anemia
- Osteoporosis and fractures
- Problems with blood clotting leading to easy bruising
- Congestive heart failure
- Pericarditis, inflammation of the heart’s outer lining
- Menstrual abnormalities and infertility
- High blood pressure
- Nerve damage in the extremities
- High potassium levels leading to cardiac arrest
Aside from these complications, each specific variant of the disease can have unique issues that can be addressed to improve the patient’s quality of life:
- The UMOD mutation can result in high levels of uric acid and gout
- The REN mutation can result in anemia, high levels of uric acid, mild low blood pressure, and mild high potassium levels
- The HNF1B mutation can result in early-onset diabetes, unclear liver function abnormalities, genito-urinary tract abnormalities, high levels of uric acid with gout, and low levels of magnesium
- The SEC61A1 mutation can result in anemia and low white blood cell count leading to abscess formation
Preventing Autosomal Dominant Tubulointerstitial Kidney Disease
Individuals diagnosed with a genetic kidney disease known as autosomal dominant tubulointerstitial kidney disease should be made aware of the inheritable nature of their condition. Doctors and other healthcare professionals should communicate clearly that there aren’t any existing medications to cure the root cause of this disease.
The primary goal of treating this disease should be preventative action that slows the progression of the disease towards End Stage Renal Disease (ESRD) – a condition in which the kidneys stop working completely, and management of disease-related symptoms.
Doctors should also highlight the critical role of proper medication use and ongoing compliance with the recommended wellness plan. The disease is passed down in families with a dominant gene, meaning other family members are at a risk of having the disease even if they don’t show any symptoms. Therefore, it is logical to perform genetic tests on other family members to identify potential carriers of the disease.
