Rare kidney diseases are hereditary and affected individuals do not have the CLCNKB gene, which is responsible for a specific chloride channel. The electrolyte balance is disrupted because i kidneys they fail to reabsorb important nutrients and salts into the bloodstream during urine filtration and production.
In addition to the absence of the CLCNKB gene, Beck suspected that there might be more extensive deletions – areas completely deleted from the genome – that would explain the severe clinical picture.
Finding out would require taking a closer look at the genes that cause disease, so she contacted Dr Janine Altmüller, head of the genomics platform at the Max Delbrück Center and the Berlin Institute of Health at Charité (BIH).
His team, based at the Max Delbrück Center’s Institute for Medical Systems Biology Berlin (MDC-BIMSB), pioneered cutting-edge sequencing technologies such as long-read sequencing. This technology has enabled them to analyze parts of patients’ genomes that previously could not be resolved.
The results of research were published in the magazine Genome Medicines.
Rare kidney disease: here are the details of the new research
Traditional short-read sequencing methods involve breaking DNA into many small fragments, which must then be reassembled. But when it comes to complex genomic structures, these common clinical technologies reach their limits, for example when sequences are repeated multiple times in a stretch of DNA, as is the case in Bartter syndrome type 3. This explains why no one had looked into previously genomic structures. fine-scale structure of affected genes.
Long-read sequencing, on the other hand, can accurately read much longer stretches of DNA in a single run, typically on the order of thousands or even tens of thousands of base pairs.
So the individual pieces of this gigantic puzzle made up of complex repeating patterns are larger, making it easier to put them back together correctly. It was this progress that led the journal Nature Methods to name long-read sequencing its Method of the Year in 2022.
Using this technology, Altmüller’s team of scientists has now identified several previously unknown genetic variants affecting CLCNKB and the neighboring gene CLCNKA.
Their study included a cohort of 32 patients from renal centers in Cologne, Marburg, Münster and London. “In one of the recently discovered structural variants, a small section of one gene is located in a similar position in the neighboring gene,” explains Altmüller. This genetic pattern has no immediate effect on the kidneys and was present in nearly half of the healthy control individuals. But it was almost always present in patients with Bartter syndrome.
Researchers suspect that this pattern in the genome favors the emergence of disease-causing genetic variants. “Structural change is fascinating because, in evolutionary terms, it is a mutation hotspot,” says Altmüller.
“The model increases the likelihood that other structural variants could emerge during human evolution.” In fact, the team found eight different deletions in CLCNKB in the patient cohort. This means, Altmüller says, that rare kidney disease doesn’t always result from the same structural variants, but instead involves independent events that share the same genetic background.
The researchers found no further deleted sequences in the Syrian family. So Bartter’s syndrome type 3 remained the only diagnosis. “We rarely see such an unusually severe disease course in our healthcare system,” explains Beck. “This is because kidney failure is usually detected much earlier, so late-stage effects, such as those that show up in the joints, can usually be prevented.”
The findings will help scientists better understand the causes of the disease. Such knowledge can also facilitate the development of better diagnostic and treatment options. Altmüller has already taken the first step towards translating the technology into clinical practice.
“A pilot study with partners from Berlin, Hanover, Tübingen and Aachen will soon begin in which we want to apply long-read sequencing to a larger cohort of patients with unresolved rare genetic diseases.”
Rare kidney disease, also known as chronic kidney disease, occurs when long-term damage to the kidneys prevents them from working properly. The kidneys filter and clean the blood by removing toxins through urine and excretions. When the kidneys don’t work properly, waste builds up in the body, causing health complications.
Most rare kidney diseases are hereditary, while some have complex causes. Hereditary kidney diseases are difficult to diagnose, manage and treat, especially when they cause other problems. Kidney problems often start with small cysts and infections that get worse over time.
Almost all children with rare kidney disease receive renal replacement therapy. At least 10%¹ of adults have inherited kidney disease, which is the fifth most common cause of end-stage renal disease, after conditions such as glomerulonephritis, pyelonephritis and diabetes. Patients sometimes spend years consulting with different medical professionals before getting a definitive diagnosis.
In the United States, kidney disease is rare when it affects fewer than 200,000 Americans. In Europe, a condition is rare when it affects fewer than 2,000 people.
Kidney failure is not a disease: it is the end stage of chronic kidney disease. Your doctor will diagnose kidney failure when kidney function is reduced to 10-15%. At this point, you need a kidney transplant or dialysis to keep you alive.
There are about 150 different rare kidney diseases. These diseases have a high prevalence worldwide, with approximately 60-80 cases per 100,000 people in America and Europe.
Abnormal hemolytic uremic syndrome (aHUS) is one of the more unusual kidney diseases. This condition can occur at any stage of life and causes blood clots in the tiny veins of the kidney.
These clots can cause serious clinical problems if they restrict blood flow. The three main features of aHUS are low platelet counts, red blood cell death, and kidney failure.
Polycystic kidney disease is often hereditary and causes cysts on the kidneys and other internal organs. Over time, these cysts impair kidney function, which can ultimately lead to kidney failure. Although treatments slow the growth of these cysts, PKD has no specific cure.
Fabry disease is a rare, heritable kidney disease. It affects all organs in the body, including the kidneys, heart and brain, and can cause them to get less blood than they need. Eventually, kidney failure or chronic kidney disease may occur.
Glomeruli are blood vessels in the kidneys that support the filtering system. Glomerulonephritis damages the glomeruli, making them unable to do their job. Eventually, kidney failure can occur. The underlying medical problem affects how your doctor diagnoses and treats this condition.
IgA is an antibody produced by the immune system. In IgA nephropathy, these antibodies build up and damage the glomeruli of the kidneys. This condition often goes undiagnosed and it may take some time to reverse the damage. IgA nephropathy can eventually lead to kidney death, kidney failure, or ongoing kidney damage. While there is no known treatment for IgA nephropathy, medications can delay the damage.
Another extremely rare type of kidney disease is C3 glomerulopathy (C3G). C3 is an immune system protein, and just like IgA nephropathy, accumulation of this protein in the kidneys causes damage to the glomeruli. The main causes or triggers of C3G are infections, genetic factors and abnormal accumulation of proteins in the blood.
Cystinosis is rare and heritable causes the body to build up crystals of cystine, an amino acid. It mainly affects the kidneys and eyes, but can affect any area of the body. The renal type occurs most often in childhood.
Treatments for this condition include cystine-depleting therapies and kidney transplants. Without prompt treatment, cystinosis could lead to kidney failure.
Many of these diseases are silent, and diagnosing rare kidney disease can be difficult. Not only can the symptoms indicate other conditions, but the signs don’t appear until the disease has progressed, causing damage to the kidneys.
You may have rare kidney disease if you have high blood pressure or diabetes. Your doctor may check your kidneys at least once a year with a screening blood test. The test can check your creatinine levels and estimated glomerular filtration rate (GFR) to see how well your kidneys are working.
Some of these signs may indicate rare kidney disease:
Swelling of the feet and hands: If the kidneys don’t remove enough sodium and excess water from the body, the feet or other lower areas may swell.
General body weakness: Toxins can build up in the blood due to impaired kidney function, depleting energy and making you feel tired.
Shortness of breath: If your kidneys don’t get enough water out of your body, it could build up in your lungs and make you feel breathless.
Spine and Back Pain: Kidney problems can cause chronic back pain as they occur on both sides of the spine in the lower back.
If you experience these symptoms, you should see a nephrologist or primary care physician. A nephrologist is a kidney expert who can diagnose you, create an individual treatment plan, and discuss treatment for rare kidney diseases with you.
Having one of the rare kidney diseases can be difficult. While there is no specific cure for most people, it is now possible to live longer and healthier lives with rare kidney disease. Technological advances and new medical interventions are accelerating our understanding of rare kidney diseases.
To protect your kidneys, adopt a healthier lifestyle and get regular checkups.
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