Of the 46 chromosomes in each cell, half are inherited from the mother and half from the father. The genes are encoded in the chromosomes. The genes on chromosomes 1 (MUC1 and REN), 16 (UMOD), and 17 (HNF1B) are crucial for ADTKD. If one parent has a mutation, the children, regardless of gender, have a 50% risk of inheriting this mutation (Fig. 2). If this is the case, there is a high probability that the disease will develop during adulthood and ultimately lead to kidney failure. In MUC1 and UMOD, the disease is limited to the kidney. Although the same mutation is inherited within a family, the timing of onset and the dynamics of the disease progression can vary considerably.
ADTKD-WEBINAR
Those affected can advance research
The first webinar for those affected by Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) in Germany took place in December 2024. Prof. Dr. Michael Wiesener, an ADTKD expert from the University Hospital Erlangen, provided a comprehensive overview of the causes and symptoms, genetic diagnostics, and the current state of research on possible therapies. A European ADTKD registry is currently being established, which requires as many patients as possible.
What does ADTKD mean?
The abbreviation stands for “Autosomal Dominant Tubulointerstitial Kidney Disease”.
Autosomal: The gene for the inherited mutation is not located on one of the two sex chromosomes, but on one of the other 22 pairs of chromosomes (the autosomes). This means that the mutation is inherited regardless of sex.
Dominant: In dominant inheritance, a single defective gene from either parental gene leads to disease symptoms, even if the other parental gene is intact. The risk of inheritance is therefore statistically 50%.
Tubulointerstitial: The cells of the renal tubules and the space surrounding them (interstitial) are affected.
ANATOMY AND FUNCTION OF THE KIDNEY
Prof. Wiesener explained the anatomy and function of the kidneys. Their primary function is to detoxify the body and regulate fluid and electrolyte balance. Approximately 1,500 liters of blood flow through the kidneys every day. This blood is filtered in the nephrons, the smallest functional units of the kidney. They consist of glomeruli and the connected tubules (Fig. 1). Approximately 180 liters of urine are filtered every day, but only 1.5 liters are excreted as urine, as water and many of the substances dissolved in it must be reclaimed for the body's disposal.
Fig. 1: Structure of the kidney and a nephron (BioRender)
SYMPTOMS AND COURSE OF THE DISEASE
In ADTKD, the final segment of the renal tubules, the distal tubule, is affected (Fig. 1). In this region, defective proteins produced by mutated genes accumulate in the cytoplasm. Since this "protein waste" can no longer be removed, the cell gradually becomes clogged and ultimately dies.
Increasing kidney weakness (renal insufficiency) usually progresses slowly. It is initially evident as a rising creatinine level in the blood. Urine examinations are inconspicuous in ADTKD. Usually, neither protein (proteinuria) nor blood (hematuria) is found. Ultrasound scans rarely reveal abnormalities; the kidneys are normal in size or relatively small. Cysts may be present, but they are not a specific feature of ADTKD. As the disease progresses, blood pressure increases. Gout can occur in UMOD. A biopsy will reveal scar tissue in the tubules, but this can indicate various diseases.
WHICH GENES ARE AFFECTED?
ADTKD is a monogenic disease. This means it is caused by a mutation in a specific gene. There are various genes that can be mutated in ADTKD. What almost all of them have in common is that they result in the formation of "incorrect" proteins. The most commonly affected genes are UMOD and MUC1, affecting about 90% of cases, while REN and HNF1B are significantly less common. The mutation can be located at different sites, meaning there are multiple variants within a gene. The type of variant may determine whether the disease is mild or severe.
Summary: Causes, symptoms and inheritance
- ADTKD is caused by a mutation in a specific gene, the most commonly affected genes being UMOD and MUC1.
- The disease primarily affects the kidneys. Both kidneys are always affected.
- The disease is not noticeable in its early stages. The first sign may be an increase in creatinine levels. Urine is usually unremarkable.
- The probability of inheriting ADTKD is 50%.
- ADTKD can only be reliably diagnosed with a genetic test, which eliminates the need for a biopsy.
HOW CAN THE START OF DIALYSIS BE DELAYED?
General measures and certain medications can slow the progression of kidney disease and thus also ADTKD.
What can I do myself?
The same recommendations apply here as for all other kidney diseases:
- Try to achieve or maintain a normal weight.
- Eat a balanced diet. A Mediterranean diet is generally considered to be beneficial to health.
- Regular physical activity also has a positive effect on overall health.
- Avoid nicotine.
- Check your blood pressure regularly. It should be within the normal range (<130/<80 mmHg).
- Avoid over-the-counter painkillers such as nonsteroidal anti-inflammatory drugs (e.g., ibuprofen or diclofenac), especially if your creatinine level is already elevated.
Kidney-protective medications
Optimal
blood pressure reduction can be achieved with medications from the group of ACE inhibitors (e.g., ramipril) or AT1 receptor blockers (e.g., sartans). These substances not only lower blood pressure but also have nephroprotective properties. They can
slow the process of kidney scarring (fibrosis). Early use of these medications is recommended even for mildly elevated blood pressure.
SGLT2 inhibitors are a relatively new class of medications. They can slow the progression of disease in various forms of kidney failure. However, they have not been specifically tested for ADTKD. Currently, SGLT2 inhibitors are recommended for all chronic kidney diseases. One side effect is an increase in creatinine, which is artificially induced by the medication. This process is reversible when the medication is discontinued.
For patients whose kidney function fails despite all measures, kidney transplantation is the best option as an alternative to dialysis. It not only improves the medical prognosis but also the quality of life. ADTKD does not transfer to the new kidney. Unfortunately, Germany ranks particularly poorly in the area of organ donation compared internationally. The waiting time for a kidney transplant is very long, averaging 9 to 10 years. Particularly good results are achieved with living donations. In the case of a living donation from a family member, genetic testing must be performed beforehand to ensure that the potential donors are not also affected by ADTKD.
SPECIFIC THERAPY APPROACHES FOR ADTKD
International research is currently underway into various therapies for ADTKD. The most promising are a substance that removes the accumulated proteins from the cells and a technology that prevents these proteins from forming in the first place.
Substances: BRD4780
An approach to removing mutated proteins from renal tubule cells was developed at the Broad Institute in Boston. Researchers discovered that the substance BRD4780 can degrade these proteins. Although it showed promise in cell and animal models, it encountered a setback in the preclinical phase. Severe side effects occurred during animal testing. Nevertheless, the mechanism remains compelling, and new substances with a similar mode of action but better tolerability are currently being tested.
RNA-based therapy (siRNA)
A second approach is based on the use of siRNA (small interfering RNA). This technology is already approved for other diseases, such as elevated LDL cholesterol levels. It allows the targeted destruction of the RNA responsible for the formation of the mutated protein. Prof. Wiesener emphasized that this is not gene therapy. The reversible process targets exclusively the RNA without altering the genetic material.
The RNA encoding the mutated protein is recognized by specific siRNA molecules. This siRNA binds to the target RNA and causes it to be degraded by the cell's own enzymes. This stops the production of the mutated protein. One of the most important challenges is to deliver the siRNA specifically into the affected cells. According to Prof. Wiesener, it will take several years before such a therapy is available.
PRE-IMPLANTATION GENETIC DIAGNOSIS (PGD)
PGD is a procedure that allows the genetic testing of embryos after in vitro fertilization before they are transferred into the uterus. Couples with genetic predispositions can use this procedure to prevent serious hereditary diseases from being passed on. PGD can also be used for ADTKD. During PGD, genetic testing of cells from the blastocyst (an early stage of embryo development) is performed after in vitro fertilization (IVF). After approximately five days, five to six cells are removed and genetically analyzed. Embryos that do not carry the genetic predisposition for the disease in question can be implanted in the uterus.
Summary: Supportive measures & potential therapies
- Those affected can positively influence the course of the disease through a healthy lifestyle. Painkillers such as ibuprofen or diclofenac should be avoided.
- Good blood pressure control with values <130/<80 mmHg is particularly important. In cases of hypertension, ACE inhibitors or AT1 receptor blockers should be used early.
- SGLT2 inhibitors may also help slow disease progression. However, there are no studies specifically demonstrating this in ADTKD.
- A kidney transplant is currently the best treatment option for definitive kidney failure.
- International research is underway into specific therapies for ADTKD. Promising approaches include the substance BRD4780 and RNA-based technologies.
- Since ADTKD is a serious hereditary disease, those affected who wish to have children can benefit from prenatal diagnostics.
PATIENT REGISTRY ADTKD-Net
The European ADTKD Registry is a crucial step in advancing research and therapy development. The more patients actively participate, the better and faster progress can be made. This will especially benefit the next generation of patients. A three-year grant has been approved for the ADTKD.net registry. Numerous European partners from countries such as Belgium, France, Italy, the Czech Republic, and Cyprus are involved.
Registry data provides important insights into the disease and its natural course. It is also essential for proving the efficacy of potential drugs. Regulatory authorities require sound evidence, which can only be provided by the largest possible number of registered patients. Such a register already exists in the USA.
Genetic testing is a key component in identifying those affected. If there is a suspicion, this can be arranged via a GP or nephrologist or in the human genetics department of a clinic. If the familial mutation is already known, a targeted test is sufficient. Every potentially affected person has the right to be informed about their genetic predisposition or to deliberately choose not to do so. Children may not be tested.
In addition to the regularly recorded data, such as the type of mutation or creatinine levels, blood and urine samples are collected as part of the registry. This is important in order to identify biomarkers that can be used to prove the effectiveness of future therapies. Research can also be carried out on the urine cells. If you have any questions about inclusion in the registry, please contact :
or
PATIENT ORGANIZATION: ADTKD Vision Cure
Christian Scheidler, chairman of the Vision Cure ADTKD association, introduced the patient association. The primary goal of their work is a treatment.
ADTKD is little known among many physicians, including those in the nephrology field, and is often confused with PKD (polycystic kidney disease). The patient association maintains a website, has developed flyers, and regularly participates in conferences to raise awareness of the disease.
The website, which is also available in English, receives inquiries from various countries. These are forwarded to specialized physicians. Another focus is the search for new patients. Because the disease can only be diagnosed through a genetic test and is particularly difficult in cases of MUC1, it often goes undetected. Targeted educational efforts aim to reduce the number of unreported cases. The association also actively engages with the pharmaceutical industry to raise interest in ADTKD and advance the development of therapies. The organization maintains close contact with the US-based ADTKD Patient suport group and actively supports the ProTransplant alliance, which is committed to improving organ donation in Germany.
Christian Scheidler believes that research into ADTKD is not a given when it comes to rare diseases, and this gives hope. A drug trial is expected in the coming years. The association supports the establishment of the registry to achieve the necessary patient numbers for these studies.
The association offers a newsletter and is interested in those affected who would like to share their personal stories with ADTKD (anonymously). These accounts offer valuable insights to other affected individuals and can help them come to terms with their diagnosis. If you are interested, please send an email to info@adktk.de. The association also welcomes donations:
Summary: ADTKD Register & Self-Help
- A European registry for ADTKD patients is currently being established. It is one of the most important prerequisites for conducting clinical trials with potentially effective therapies. Success depends largely on the participation of as many affected individuals as possible.
- There is a patient support organization whose goal is to develop a therapy for ADTKD. The ADTKD Vision Cure association has a comprehensive website with information for patients and physiacians in German and English, is internationally networked, and participates in conferences.