Medullary cystic kidney disease

Medullary cystic kidney disease has an autosomal dominant pattern of inheritance.

Medullary cystic kidney disease (MCKD) is an autosomal dominant kidney disorder characterized by tubulointerstitial sclerosis leading to end-stage renal disease. While the name is misleading, recent research has shown that the presence cysts is not pathognomonic of the disease. For this reason, it has been recently referred as the more accurate, medullary kidney disease.^[1][2] Importantly, if cysts are found in the medullary collecting ducts they can result in a shrunken kidney, unlike that of polycystic kidney disease. There are two known forms medullary cystic kidney disease, MKD1 and MKD2^[1]

MKD1/Mucin-1 kidney disease

• Overview Mucin-1 kidney disease is due to a mutation within the MUC1 gene, which is located on Chromosome 1. The MUC1 gene codes for a glycoprotein, Mucin1, that is expressed in many tissues in the body. It is involved in the creation of a mucus-like substance that coats the surface of different small tubules in the body. It is expressed on distal tubular cells in the kidney. Mucin-1 kidney disease (MKD) is caused by a mutation in the MUC1 gene.^[3] This mutation alters the genetic sequence in the MUC1 gene, resulting in a new, mutated protein. This disease is extremely rare and only affects approximately 1,000 families in the world, with 100 of those being know to reside in the United States. This disease is autosomal dominant, meaning that it is characterized by a 50% chance of inheritance and slowly progressive chronic kidney disease that leads to the need for dialysis or a kidney transplant. Patients with a mutation in this gene can have a variable rate of loss of kidney function, with some individuals going on dialysis in their thirties while others may not go on dialysis until into their 70’s.
• Terminology: There have been many names for this disease, leading to a lot of confusion and often missed diagnosis. Earlier on the condition was called medullary cystic kidney disease type 1. It was named this because some people with the disease had cysts (small holes) in the middle (medulla) of their kidneys. It has since then been found that these cysts are uncommon and are not found in the majority of the patients with MUC1 mutations. For this reason, this name has been abandoned. A group of scientists (part of the Kidney Dialysis Initiatives and Global Outcomes (KDIGO) ^[4] group) specializing in this disease came together formally and created an official name for this and similar conditions. This condition was designated as Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) due to mutations in Mucin-1. Autosomal dominant means that 50% of children of an affected individual will inherit the disease. Tubulo-interstitial is used because the problems that occur in this disease happen in the compartment of the kidney known as the tubulo-interstitium. A shorter name of the disease is to be used by most doctors and patients: mucin-1 kidney disease (MKD).
• Clinical presentation: This disease is often hard to diagnose because there are few symptoms, and the disease is uncommon. There are only two characteristics of the disease:
  • (1) Chronic kidney disease. The kidney filters the body’s waste products. In this condition, loss of kidney function occurs slowly over time. As in most kidney diseases, patients do not have any symptoms of kidney disease until only 10% of normal kidney function remains. Thus, most patients have no symptoms of kidney failure until they are close to dialysis or need a kidney transplant. Symptoms at this time include fatigue, nausea and vomiting.
  • (2) Inheritance. Each person has two genes for each protein that is made in the body. One gene comes from the mother and one from the father. In UKD, patients have one abnormal gene and one normal gene. If a patient has UKD, he has a 50% chance of passing on the abnormal gene to his child. Thus, his child has a 50% chance of having the disease. Given that 50% of children of an affected individual will have the disease, there are often many family members with the disease, and at least a parent and child usually have the disease.
• Diagnosis:
  • (1) Doctors often obtain a routine blood test called the serum creatinine. Creatinine is a breakdown product from the muscle. As kidney function declines, the amount of blood creatinine goes up. Thus, most affected individuals have no symptoms of MKD, but find out that they have the condition due to an elevation in the blood creatinine level.
  • (2) When a urine test is done for this disease, there is almost never any blood and usually little amounts or no protein present in the urine. This is in contrast to many diseases that have both. A kidney ultrasound in this condition usually shows normal or small sized kidneys (occasionally cysts are present). However, since cysts are present in many normal individuals, these cysts are not helpful in making a diagnosis. Doctors can also do a kidney biopsy in this disease. Kidney biopsy is a procedure where the kidney doctor inserts a needle into the kidney and removes a small piece of kidney tissue. This tissue is then examined under a microscope. Unfortunately, a biopsy cannot make a definite diagnosis of this disease, and it is therefore not recommended to diagnose MKD.^[1]
  • (3) Definitive testing and diagnosis of MKD can be made by analyzing the MUC1 gene for mutations. This can be done by a blood test. The test is only available on a research basis at present.
  • (4) A tentative diagnosis of the disorder can be made if the following is present: (a) A family member also has kidney disease and has had a genetic diagnosis of MKD. (b) The patient has an elevated serum creatinine level, and (c) there are no signs of other kidney disease, such as blood or protein in the urine.
• Etiology:

A normal healthy patient has two copies of the MUC1 gene that each function the same way. The genes produce the protein mucin-1. This protein is expressed only in certain cells in the kidney – the thick ascending limb of Henle and distal convoluted tubule – both parts of the kidney tubule. The protein coats the surface of the tubule and protects the tubule. In MKD, patients have one normal and one abnormal MUC1 gene. The abnormal gene produces an abnormal protein product that cannot fold properly into its final structure. This abnormal protein deposits within the cell (in a part of the cell called the endoplasmic reticulum). The abnormal protein builds up in the cell and causes it slowly to die. The tubule cells in the kidney slowly die, and the kidney also loses its function and slowly dies, leading to chronic kidney disease. There is a lot of variation in the age of onset of kidney failure, with some individuals going on dialysis in their 30’s and some not starting dialysis until later than their 70’s.^[1][3] Scientists do not understand why this variation occurs.

• Research:

In 20xx, doctors and scientists from the Broad Institute, Cambridge, Massachusettsidentified the genetic cause of UKD as mutations in the UMOD gene.^[3] Since that time, scientists have been studying the disease and trying to find a treatment for this condition. Facilities with a significant clinical interest in UKD include: -Wake Forest School of Medicine, Winston-Salem, NC, USA -Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University, Prague, the Czech Republic At present, a research trial is being conducted at Wake Forest School of Medicine to identify why there is such a great variation in the age of onset of kidney failure. Scientists hope to use this information to come up with a treatment for the disease. Patients provide a blood sample that is sent via mail to Wake Forest, and scientists at Wake Forest check for genetic variations that may be responsible for the differences in age of onset.^[1]

• Treatment:

At present there are no specific therapies for this disease. There are no specific diets known to slow progression of the disease. Anthony Bleyer, M.D. and Wake Forest University are working towards finding a treatment and are likely to begin a clinical trial of a medicine to slow progression of kidney disease in the near future.^[1]

• For information about how to get tested for MCKD1 or to join a research study, visit: www.wakehealth.edu/Nephrology/Medullary-Kidney-Disease/Research-Team-Mucin-1-Kidney-Disease.htm
• For information about kidney donations or how to become a donor: www.kidney.org/transplantation/livingdonors

MKD2/Uromodulin kidney disease

• Overview Inherited mutations (mistakes) in a gene named UMOD that encodes a protein called uromodulin (also known as Tamm-Horsfall protein) cause an inherited kidney disease.^[5] This disease is also autosomal dominant, meaning that it is characterized by a 50% chance of inheritance and slowly progressive chronic kidney disease that leads to the need for dialysis or a kidney transplant. Many – but not all – patients and families with this disease suffer from gout relatively early in life. Patients with a mutation in this gene can have a variable rate of loss of kidney function, with some individuals going on dialysis in their thirties while others may not go on dialysis until into their 70’s.^[2] This is a rare inherited kidney disease that exists in less than 1% of people with kidney disease.
• Terminology: There have been many names for this disease, leading to a lot of confusion and often missed diagnosis. Earlier on the condition was called medullary cystic kidney disease type 2. It was named this because some people with the disease had cysts (small holes) in the middle (medulla) of their kidneys. It has since then been found that these cysts are uncommon and are not found in the majority of the patients with UMOD mutations. For this reason, this name has been abandoned. This condition also was called familial juvenile hyperuricemic nephropathy. It was given this name because many individuals had a high blood uric acid level and developed kidney failure when young. However, older patients also develop the disease, and not all have high uric acid levels. For this reason, a group of scientists (part of the Kidney Dialysis Initiatives and Global Outcomes (KDIGO)) ^[4] came together formally and created an official name for this and similar conditions. This condition was designated as Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) due to mutations in Uromodulin. "Autosomal dominant"* means that 50% of children of an affected individual will inherit the disease. "Tubulointerstitial" is used because the problems that occur in this disease happen in the compartment of the kidney known as the tubulo-interstitium*. A shorter name of the disease is to be used by most doctors and patients: uromodulin kidney disease (UKD).
• Clinical Presentation:

There are three characteristics of the disease:

• • (1) Chronic kidney disease. The kidney filters the body’s waste products. In this condition, loss of kidney function occurs slowly over time. As in most kidney diseases, patients do not have any symptoms of kidney disease until only 10% of normal kidney function remains. Thus, most patients have no symptoms of kidney failure until they are close to dialysis or need a kidney transplant. Symptoms at this time include fatigue, nausea and vomiting.
  • (2) Gout. Some – but not all – individuals with this disease develop gout.^[2] Gout is a condition in which patients develop severe pain and swelling in the big toe or another joint such as the knee. This pain lasts several days to a week before it goes away. If gout is untreated, it becomes chronic and affects the joints most of the time instead of intermittently.
  • (3) Inheritance. Each person has two genes for each protein that is made in the body. One gene comes from the mother and one from the father. In UKD, patients have one abnormal gene and one normal gene. If a patient has UKD, he has a 50% chance of passing on the abnormal gene to his child. Thus, his child has a 50% chance of having the disease. Given that 50% of children of an affected individual will have the disease, there are often many family members with the disease, and at least a parent and child usually have the disease.
• Diagnosis:
  • (1) Doctors often obtain a routine blood test called the serum creatinine. Creatinine is a breakdown product from the muscle. As kidney function declines, the amount of blood creatinine goes up. Thus, most affected individuals have no symptoms of UKD, but find out that they have the condition due to an elevation in the blood creatinine level.
  • (2) Affected individuals also have an elevation in the blood uric acid level. In UKD, the kidney has difficulty getting rid of uric acid due to the mutation. The doctor can find out that the uric acid level in the blood is high when he does a blood test. Gout is caused by high uric acid levels, and thus patients often have gout.
  • (3) When a urine test is done for this disease, there is almost never any blood and usually little amounts or no protein present in the urine. This is in contrast to many diseases that have both. A kidney ultrasound in this condition usually shows normal or small sized kidneys (occasionally cysts are present). However, since cysts are present in many normal individuals, these cysts are not helpful in making a diagnosis. Doctors can also do a kidney biopsy in this disease. Kidney biopsy is a procedure where the kidney doctor inserts a needle into the kidney and removes a small piece of kidney tissue. This tissue is then examined under a microscope. Unfortunately, a biopsy cannot make a definite diagnosis of this disease, and it is therefore not recommended to diagnose UKD.
  • (4) Definitive testing and diagnosis of UKD can be made by analyzing the UMOD gene for mutations. This can be done by a blood test. The test can be expensive and is not always covered by insurance.
  • (5) A tentative diagnosis of the disorder can be made if the following is present: (a) A family member also has kidney disease and has had a genetic diagnosis of UKD. (b) The patient has an elevated serum creatinine and elevated uric acid level, and (c) There are no signs of other kidney disease, such as blood or protein in the urine.
• Etiology:

A normal healthy patient has two copies of the UMOD gene that each function the same way. The genes produce the protein uromodulin. This protein is expressed only in certain cells in the kidney – the thick ascending limb of Henle* – a part of the kidney tubule. The protein coats the surface of the tubule and keeps it water-tight. In UKD, patients have one normal and one abnormal UMOD gene. The abnormal gene produces an abnormal protein product that cannot fold properly into its final structure. This abnormal protein deposits within the cell (in a part of the cell called the endoplasmic reticulum). The abnormal protein builds up in the cell and causes it slowly to die. The tubule cells in the kidney slowly die, and the kidney also loses its function and slowly dies, leading to chronic kidney disease. There is a lot of variation in the age of onset of kidney failure, with some individuals going on dialysis in their 30’s and some not starting dialysis until later than their 70’s. Scientists do not understand why this variation occurs. Gout often occurs in this disease. The cause of gout is somewhat complicated. Loss of normal uromodulin function makes the kidney tubule leak sodium into the urine. The front part of the tubule (proximal tubule) compensates for this by increasing sodium intake. The increase in the sodium reabsorption is associated with an increase in uric acid absorption, leading to high blood uric acid levels. Some, but not all, patients with high blood uric acid levels develop gout.

• Research:

In 2001, doctors and scientists from the Wake Forest School of Medicine in Winston-Salem, NC identified the genetic cause of UKD as mutations in the UMOD gene.^[5] Since that time, scientists have been studying the disease and trying to find a treatment for this condition.

• • • Facilities with a significant clinical interest in UKD include:
    • -Wake Forest School of Medicine, Winston-Salem, NC, USA
    • -Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University, Prague, the Czech Republic
    • -Centre de Genetique Humaine, Institut de Pathologie et de Genetique, Gosselies, Belgium
    • -Dulbecco Telethon Institute, San Raffaele Institute, Milan, Italy
    • -Norfolk and Norwich University Hospital, Norwich, UK
    • -Academic Endocrine Unit, Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, and University of Oxford, Oxford, UK

As result of this recent research, there have been over 100 different mutations discovered in the UMOD gene that cause UKD. Scientists are trying to find a treatment for this disease. More information can be found on the UKD Cure Foundation website. At present, a research trial is being conducted at Wake Forest School of Medicine to identify why there is such a great variation in the age of onset of kidney failure. Scientists hope to use this information to come up with a treatment for the disease. Patients provide a blood sample that is sent via mail to Wake Forest, and scientists at Wake Forest check for genetic variations that may be responsible for the differences in age of onset.

• Treatment: At present there are no specific therapies for this disease. There are no specific diets known to slow progression of the disease. If patients develop gout, this can be treated with a medication called allopurinol. At one time, doctors thought that allopurinol would slow the rate of kidney decline in all patients with this disease; however, there is not enough data to tell for sure if allopurinol slows progression.

Other resources include the National Kidney Foundation, the National Organization for Rare Disorders (NORD), and Wake Forest School of Medicine.^[6]

See also

• Nephronophthisis

References

External links

• GeneReviews/NCBI/NIH/UW entry on UMOD-Related Kidney Disease Includes: Familial Juvenile Hyperuricemic Nephropathy, Medullary Cystic Kidney Disease 2
• OMIM entries on UMOD-Related Kidney Disease Includes: Familial Juvenile Hyperuricemic Nephropathy, Medullary Cystic Kidney Disease 2