ADTKD -
the Disease
WHAT IS ADTKD?
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic disease. It is inherited in an autosomal dominant manner. This means that one parent has an altered (mutated) gene that causes chronic deterioration in kidney function. There is a 50% chance that this gene mutation will be passed on to children. It is passed directly from generation to generation. If there is a cluster of diseases in a family, this can be an indication of an inherited disease. However, the course varies greatly from person to person.
WHAT VARIANTS OF ADTKD ARE THERE?
In ADTKD, different genes can be altered. Depending on which gene is affected, a distinction is made between subtypes. The most common genes are:
- Mucin-1 (MUC1 mutations; Abbreviation: ADTKD-MUC1, MKD)
- Uromodulin (UMOD mutations; Abbreviation: ADTKD-UMOD)
- Hepatocyte Nuclear Factor 1beta (HNF1B mutations; Abbreviation: ADTKD-HNF1B)
- Renin (REN mutations; Abbreviation: ADTKD REN)
WHAT CAUSES THE ADTKD FORMS MUC1 AND UMOD?
Both diseases are based on a similar mechanism. Due to the disease-causing change in the two genes (mutation), a slightly modified protein is formed by the kidney cells. Since this protein is only insufficiently degraded, it is deposited in large quantities in the tubule cells, which leads to cell damage. The result is a gradual scarring (fibrosis) of the kidney tissue. This ultimately leads to the kidney no longer being able to perform its functions. These include the regulation of fluid and electrolyte balance, blood pressure, acid and alkaline balance, detoxification of the body, the formation of red blood cells and the regulation of bone metabolism. Both kidneys are always affected.
MUC1 disease is caused by a mutation in the MUC1 gene. MUC1 (mucin 1) is a protein that is produced in many body cells of different organs, for example in the stomach or lungs. However, the mutation only causes problems in the kidneys. It is not yet known why this is so.
UMOD disease is caused by mutations in the UMOD gene. In contrast, the protein UMOD (uromodulin) is actually only produced in the kidney and mutations therefore only manifest themselves as a disease there in affected patients.
Among all forms of ADTKD, MUC1 disease accounts for about 30-40%, UMOD disease is perhaps slightly more common. Usually, several family members are affected, almost always at least one parent and one child.
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SYMPTOMS: HOW DOES ADTKD INDICATE?
As the name suggests, ADTKD affects the tubules, i.e. the kidney tubes. Tubules are tubular structures in kidney tissue that are involved in regulating water and electrolyte balance. ADTKD can remain asymptomatic for a long time. Over time, chronic kidney disease develops. The first signs can be high blood pressure or an elevated creatinine level in the blood. This is often discovered by chance during other examinations and indicates that the kidney function is limited. Only in the advanced stage do symptoms develop that are generally observed in kidney diseases.
These include for example:
- high blood pressure
- Anemia
- water retention (oedema)
A typical feature of ADTKD is that, apart from kidney failure, it has hardly any other characteristic features. Gout can develop in ADTKD-UMOD. Thus, in contrast to other kidney diseases, there is usually no or only little protein in the urine. Cysts can occur, but only in small numbers and are not typical of ADTKD. This makes the
diagnosis more difficult.
HOW IS ADTKD DIAGNOSED?
If there is an increase in the creatinine level in the blood, a
urine test is usually carried out. This is often
unremarkable in ADTKD, i.e. the urine contains no blood and little or no protein. The uric acid level in the blood is also usually not elevated at the beginning of the disease. Since no specific abnormalities can be found even with an ultrasound examination of the kidneys and a kidney biopsy, the cause of the decrease in kidney function often remains unclear. However, if other people in the family are or have been affected by chronic kidney disease, this is the
most important indication of a possibly inherited disease. ADTKD can then only be detected with a special genetic tes
For more information, see
Diagnosis.
WHO IS AFFECTED?
Women and men are affected equally often. The age range is very wide. The disease can occur as early as at the age of 20, but also as late as at the age of 70 with increasing kidney weakness (kidney insufficiency).
WHAT IS THE COURSE OF ADTKD DISEASE?
Patients with
ADTKD-MUC1 usually have
slowly progressing chronic kidney disease. Mild impairment of kidney function is often seen in the late teens/early twenties. It continues to decline with age. The age at which renal replacement therapy (dialysis or transplantation) becomes necessary varies widely: some people require it as early as age 17, while other family members may go without it until age 70. The reason for these differences is unclear.
HOW IS ADTKD TREATED?
Currently, there is no specific treatment for the disease. As with other chronic kidney diseases, early medical monitoring is recommended. As soon as the creatinine level in the blood is elevated, a nephrologist should be consulted in order to recognise complications such as high blood pressure or anaemia in time and to initiate appropriate countermeasures. Certain medications for high blood pressure can help to slow down the progression of kidney failure. In the final stage, only dialysis or a kidney transplant can replace the missing kidney function. Due to the particularly pronounced organ shortage in Germany, the waiting time for a kidney is currently between 9 and 11 years, while in other European countries it is sometimes only 1.5 years. The disease does not transfer to a transplanted foreign kidney.
Internationally, research is being done on specific therapies for ADTKD. Approaches to the ADTKD-MUC1 subtype are possibly the furthest along. In basic studies, a substance was found that could possibly prevent the negative effects of the MUC1 mutation. The next step is to test whether the potential efficacy is confirmed in ADTKD-MUC1 patients. This will be done as part of a clinical trial that is scheduled to start in 2023. Due to the similar mechanisms of disease development, these approaches may also be effective in ADTKD-UMOD. In Germany, there is a register in which patients with ADTKD are recorded.
Please find more information in
Research.
WHAT CAN I DO MYSELF?
Check your family tree. If several family members are or were affected by chronic kidney disease, there is a suspicion of a genetic disease. However, there are many hereditary kidney diseases. ADTKD should be considered especially if the course is slow and there are no abnormalities in the urine, in the ultrasound or in a biopsy. Diagnosis by genetic testing can only be made in a specialized center. In addition, it is recommended:
- avoiding being overweight
- making sure your blood pressure is normal (<130/<80 mmHg)
- no smoking
- taking as few common painkillers as possible (e.g. ibuprofen, diclofenac)
- avoiding iodinated contrast media in a CT scan
- in the case of advanced disease (stage III), regular check-ups in the nephrological practice to perceive
RELATED DISEASES
In many patients with chronic kidney disease, the cause is unknown. Since the term ADTKD has only existed since 2015 and the disease is sometimes difficult to diagnose (especially the MUC1 subtype), it is not uncommon for "substitute diagnoses" to be made or for misdiagnoses to occur. It is therefore particularly important for doctors to exclude similar diseases. These include polycystic kidney disease and nephronophthisis.
Polycystic kidney disease (ADPKD) is also a hereditary disease characterized by the presence of cysts in both kidneys. The increasing number and enlargement of these cysts leads to loss of normal kidney function and high blood pressure. There are forms of polycystic kidney disease in children and adults. Symptoms include an enlarged abdomen, back pain, blood in the urine (haematuria), high blood pressure and possibly weight loss. Some affected people may also have liver problems and abnormal enlargement of the spleen. Massive cysts in the kidneys are always seen in families with this condition, making it easy to distinguish from other types of kidney disease. More information is available on the page of the Association for Cystic Kidney Patients.
Nephronophthisis is characterised by slowly progressive kidney failure. The examination of the urine also shows no blood and little protein in this disease. A major difference to ADTKD is that it is inherited in an autosomal recessive manner. This means that they can skip a generation, or there is often only one person affected. Kidney failure usually occurs in childhood, with most sufferers requiring dialysis between the ages of 15 and 25. In addition, nephronophthisis often (but not always) presents with other symptoms, such as blindness and/or other deformities.
LITERATURE
Bleyer, AJ et al. Autosomal Dominant Tubulointerstitial Kidney Disease – MUC1. In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2021. 2013 Aug 15 [updated 2021 Oct 21]
Eckardt KU, et al. Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management--A KDIGO consensus report. Kidney Int. 2015 Oct;88(4):676-83
Knaup, KX., Wiesener, MS. Autosomal dominant tubulointerstitial kidney disease (ADTKD). Nephrologist 14, 112–119 (2019)
NIH GARD Information: Autosomal dominant tubulointerstitial kidney disease; Accessed at:
https://rarediseases.org/gard-rare-disease/autosomal-dominant-tubulointerstitial-kidney-disease/
(accessed on January 5, 2022)