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The majority of individuals (greater than 80%) with tuberous sclerosis complex (TSC) will develop some form of renal (kidney) disease during their lifetime. There are three particular renal disorders in TSC including renal cysts, renal angiomyolipoma and renal cell carcinoma. Renal cysts are generally small, benign asymptomatic disorders that occur in about 20 percent of individuals with TSC. Rarely the cystic disease is extensive, and the individual may experience some degree of kidney impairment and even more rarely such patients may require replacement of their renal function by dialysis or transplantation.
Renal angiomyolipomata, or angiomyolipomas, are of a greater concern because these lesions are associated with abnormal blood vessels that can lead to bleeding. Renal angiomyolipomata occur in approximately 50-80 percent of TSC patients, and approximately 80 percent of individuals will have involvement of both kidneys. Lastly, renal cell carcinoma, an extremely rare association with TSC and angiomyolipoma, is a cancerous growth of the kidney. Although it is very rare, such a lesion must be kept in mind.
The current methods to diagnosis these renal abnormalities include renal ultrasonography, CT scanning and magnetic resonance imaging (MRI). These are all non-invasive procedures that are available in almost every major medical center. The renal ultrasound provides the least detailed image of the kidney, while the MRI provides the most detailed. In general, the ultrasound is sufficient to detect both renal cysts and the fat containing angiomyolipomata, but may not provide enough detail to accurately measure and follow the renal lesions and can miss lesions that lack the fat component.
The kidneys should be scanned, preferably with MRI or CT, at the time of diagnosis, and at 2-3 year intervals if no cysts or angiomyolipomata are identified. If kidney lesions are identified, then the growth of these lesions should be followed using repeated MRI, CT or ultrasounds every year, unless the individual becomes symptomatic or the lesion has an unusual growth pattern. For patients with TSC who have mental disabilities and/or seizures that make obtaining a CT difficult if not impossible without sedation, an ultrasound of the kidneys may be sufficient to determine if kidney lesions are present and/or if there has been a change in any of the existing kidney lesions.
Often the renal cysts do not become apparent on CT scans or ultrasound until adulthood. Usually the cysts are asymptomatic. When the cysts are very numerous, renal-related signs and symptoms can arise. Hypertension can occur. Often the best drugs to use to lower the blood pressure in this situation are either angiotensin converting enzyme inhibitors or angiotensin receptor blockers. Controlling blood pressure is very important, because having an elevated blood pressure can accelerate the loss of kidney function. Sometimes kidney failure can occur and the patient would require renal replacement therapy such as dialysis or transplantation.
How kidney cysts develop is not known. The TSC genes are believed to be tumor suppressor genes. Normally, tumor suppressor genes prevent excess cell growth. When the tumor suppressor genes are inactivated by mutations, cell growth is unchecked, leading to tumors. Cysts may, therefore, be the result of excess growth of kidney epithelial cells, which form the lining of the cysts.
Recently it was discovered that some children born with TSC and severe cystic kidneys have changes in both their TSC2 gene on chromosome 16 and the gene for polycystic kidney disease (PKD1), which lies right next to the TSC2 gene. Mutations in the PKD1 gene are associated with a disease called autosomal dominant polycystic kidney disease. When both the TSC2 and PKD1 genes are affected, severe kidney cysts can develop in infancy or early childhood.
Angiomyolipomas are named because they consist of blood vessels (“angio”), smooth muscle (“myo”) and fat (“lipoma”). Usually angiomyolipomas are multiple and occur in both kidneys. The presence of fat in angiomyolipomas often allows them to be distinguished from other renal tumors by MRI, CT or ultrasound imaging. Recent studies have given urologists (surgical specialists on the urinary system) and nephrologists (medical kidney specialists) insight into the course of renal angiomyolipoma. Two particular factors appear to be somewhat predictive of the course of the disease. The two factors include the presence or absence of symptoms related to the angiomyolipoma and the size (less than 4 centimeters or greater than 4 centimeters or about 1-1/2 inches) of the growth itself.
Most, but not all individuals with tumors less than 4 cm in diameter had no symptoms, while approximately 90 percent of individuals with a tumor greater than or equal to 4 cm appeared to have symptoms. These symptoms most commonly included abdominal or back pain, nausea and vomiting and fever. For the individual who is non-verbal, this may be present as irritability and vomiting. However, bleeding or rupture rarely occurred in children; larger tumors occurred at an older age (greater than 10 years of age). It appeared in the limited number of individuals followed in one study with TSC and angiomyolipoma, in some angiomyoliopama continued to grow. The tumors that are larger in size appear to have a greater propensity for growth than the smaller tumors. The risk of hemorrhage appears to be caused by the abnormal blood vessels that can form defects called aneurysms.
Our understanding of the growth of renal angiomyolipoma and TSC is in its infancy and we will have further information in a few more years. The real danger of a large angiomyolipoma is that it can have aneurysms that can rupture and bleed. This bleeding can be significant and occasionally life threatening. Therefore, diagnosis and treatment guidelines have been proposed to initially identify which individuals have kidney involvement in TSC and then, depending on the extent (or size) of this involvement, propose either close surveillance or some form of intervention.
It is recommended that individuals with TSC have an initial diagnostic radiologic imaging evaluation with an MRI or CT scan, or an ultrasound of the kidneys to identify patients with kidney involvement. Then, depending on the size of the involvement (less than 4 cm or greater than or equal to 4 cm), further management can be recommended. Individuals with TSC and angiomyolipomas less than 4 cm would benefit from examination with either ultrasonography or CT scanning every six months to one year. If the angiomyolipoma appears to grow or become a source of symptoms, then some intervention should be entertained. This may include surgically removing the angiomyolipoma or utilizing the radiologist to perform an embolization of the artery that goes to this growth. As of April 26, 2012, adults with TSC and renal angiomyolipoma not requiring immediate surgery may be candidates for treatment with Afinitor® (everolimus) tablets to shrink and prevent further growth of angiomyolipomas. In individuals with TSC and an angiomyolipoma greater than 4 cm, because of the high risk of further growth and the development of symptoms, consideration should be given to one of these treatments.
For those who do not want to have any form of intervention, they should be aware of the type of symptoms that are associated with bleeding from the angiomyolipoma. This includes back or abdominal pain, nausea, vomiting and fever. If these growths involve both kidneys, renal failure is a possibility; however, this is relatively uncommon. If kidney function became so poor as to not sustain life, then dialysis or transplantation would be indicated.
Over the past 20 years, there have been about 25 published reports of kidney cancer occurring in individuals with TSC. Many of these reports did not include sufficient pathologic data to clearly distinguish cancer from atypical angiomyolipoma, and follow-up clinical information was also usually not included.
Drs. Bjornsson, Short, Kwiatkowski and Henske (1996) studied six individuals with kidney cancer and TSC. Their study confirmed previous reports that kidney cancer in individuals with TSC occurs on average at an earlier age than in individuals who do not have TSC. This suggests that individuals with TSC have a higher risk of kidney cancer than the general population. Some TSC-associated cancers have different microscopic features from the most common form of kidney cancer in individuals who do not have TSC.
It remains unproved that individuals with TSC have an increased risk of kidney cancer. Additional studies are needed to determine the risk of kidney cancer in individuals with TSC and how best to screen for kidney cancer.
In summary, there are multiple different pathologic entities that can affect the kidney in TSC. Angiomyolipoma is clearly the most common and likely to cause symptoms. With careful evaluation, monitoring and appropriate intervention, hopefully the individuals with TSC will not have to worry about kidney failure or kidney cancer.
National Kidney Foundation: www.kidney.org
Kidney and Urology Foundation: www.kidneyurology.org
Polycystic Kidney Disease Foundation: www.pkdcure.org
Written by Elizabeth Petri Henske, M.D., Fox Chase Cancer Center, Philadelphia, PA, David H. Ewalt, M.D., Dallas, TX, and John J. Bissler, M.D., Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
**Tuberous Sclerosis Alliance Information Sheets are intended to provide basic information about TSC. They are not intended to, nor do they, constitute medical or other advice. Readers are warned not to take any action with regard to medical treatment without first consulting a physician. The TS Alliance does not promote or recommend any treatment, therapy, institution or health care plan.
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