Alport syndrome Treatment

Until recently most doctors thought that Alport syndrome was an untreatable disease. However, experiments carried out in mice with Alport syndrome showed that several different kinds of medication could slow down loss of kidney function. Preliminary studies in people with Alport syndrome have also provided evidence that early treatment delays kidney failure. This means that Alport syndrome should be diagnosed early in childhood.

The Alport syndrome Research Collaborative developed Clinical Practice Recommendations aimed at standardizing therapy for children with Alport syndrome.  Guidelines for treatment of adults with Alport syndrome are also available.

It is very important for people with Alport syndrome to be examined regularly by a nephrologist so that effects of kidney disease, such as hypertension (high blood pressure), can be identified early and treated. Regular hearing and vision evaluation is also important.

Medication

The recommended medications for treatment of Alport syndrome interfere with several hormones that together make up what is known as the renin-angiotensin-aldosterone system, or RAAS. The RAAS normally plays a very important role in maintaining the body‘s fluid balance and blood pressure, helping to make sure that the kidneys get the blood flow necessary for good kidney function. The RAAS is overactive in various chronic kidney diseases, including Alport syndrome, and has been shown to promote scarring of the kidneys.

Medications that interfere with RAAS hormones protect kidney function in animals and people with chronic kidney diseases. Medications that interfere with RAAS hormones include:

  1. angiotensin converting enzyme (ACE) inhibitors — these medications block the production of angiotensin II, the active form of angiotensin,
  2. angiotensin receptor blockers (ARBs) — these medications block the action of angiotensin II,
  3. aldosterone inhibitors — these medications block the action of aldosterone.

Both ACE inhibitors and ARBs have been shown to slow down the loss of kidney function in mice with Alport syndrome. People who start taking an ACE inhibitor while their kidney function is still normal are older when they develop kidney failure than Alport patients who don‘t receive ACE inhibitors or are started on ACE inhibitors after they have started to lose kidney function. ACE inhibitors, ARBs and aldosterone inhibitors all reduce elevated urine protein levels in people with Alport syndrome.

Researchers are still learning about the ways in which these medications protect the kidneys of animals and people with Alport syndrome. Researchers believe there are at least two effects. First, these medications may directly prevent the formation of scar tissue in kidneys of animals and people with Alport syndrome. Second, by lowering urine protein levels these medications may prevent the harmful effects of high urine protein levels on kidney cells. These medications have relatively few and minor side effects, they are not expensive and they have been used safely in many children with kidney disease. They are available all over the world and it is not necessary to travel to a special Alport syndrome center to receive treatment with these medications.

Diagnosis in the older child enabled earlier diagnosis in the younger sibling, resulting in earlier therapy and delayed onset of ESRD by 13 years. (Image courtesy of Oliver Gross, MD)

Diagnosis in the older child enabled earlier diagnosis in the younger sibling, resulting in earlier therapy and delayed onset of ESRD by 13 years. (Image courtesy of Oliver Gross, MD)

ACE inhibitors that have been used to treat Alport syndrome patients include, but are not limited to:

  • Benazepril
  • Cilazapril
  • Enalapril (Vasotec)
  • Fosinopril (Monopril)
  • Lisinopril (Zestril, Prinivil)
  • Perinopril
  • Ramapril
  • Quinapril (Accupril)
  • Trandolapril

ARBs that have been used to treat Alport syndrome patients include, but are not limited to:

  • Candesartan (Atacand)
  • Epresartan
  • Irbesartan
  • Losartan (Cozaar)
  • Telmisartan
  • Valsartan

Spironolactone is medication used for aldosterone inhibition.

Side Effects

Both ACE inhibitors and ARBs can cause lightheadedness, especially when a person stands up quickly. Sometimes these medications need to be stopped or their doses lowered because of persistent lightheadedness or fainting, but this is unusual. ACE inhibitors and ARBs should not be taken by females who are pregnant or who can become pregnant because they can injure a developing fetus. ACE inhibitors, ARBs and aldosterone inhibitors can cause elevated blood potassium levels, but this is not a common problem in people who have normal kidney function.

A common side effect of ACE inhibitors is a cough, which may take up to a month to subside, and if one ACE inhibitor causes cough it is likely that the others will too. Coughing occurs less often with ARBs which may be used instead of an ACE inhibitor. The most serious, but rare, side effects are allergic reactions, a decrease in white blood cells, and swelling of tissues (angioedema).

Monitoring

In addition to taking ACE inhibitors and/or ARBs to control proteinuria (protein in the urine), Alport syndrome patients need to control their blood pressure and be monitored regularly. Monitoring tests include urine and blood chemistry testing. As a general recommendation, Alport syndrome patients without any kidney function problems should be monitored yearly, patients with moderate kidney function problems should be monitored every 6 months, and those with advanced kidney failure should be monitored every 1 to 3 months.

The Clinical Practice recommendations advise testing of urine protein levels in children with Alport syndrome, starting at 1 year of age and then at least annually. The test is called the urine protein“creatinine ratio. Children with urine protein“creatinine ratios above 0.2 should be treated with an ACE inhibitor with the goal of reducing the protein“creatinine ratio as much as possible. This may require a gradual increase in the dose of the medication, and may be limited by side effects such as lightheadedness.

If a child is receiving the maximum dose of the ACE inhibitor and still has high urine protein levels, the Clinical Practice recommendations suggest starting either an ARB or an aldosterone inhibitor (the choice is up to the child‘s doctor). Some nephrologists may prefer to use an ARB initially and add an ACE inhibitor if necessary to suppress proteinuria.

Other Considerations

Patients with Alport syndrome should avoid drugs that are nephro-toxic or harmful to the kidneys. This includes over the counter medicines such as non-steroidal anti-inflammatory drugs (NSAIDs) containing aspirin, ibuprofen and naproxen, as well as some decongestants. Patients should speak with their Nephrologist to get guidance on medicines that should be avoided.

Hearing and vision should also be monitored every one to two years beginning in children, particularly boys, at 7 to 8 years of age and continued regularly. Hearing aids should be prescribed as needed.

Maintaining a healthy lifestyle and a balanced diet is also beneficial. Discussion of nutritional considerations, such as sodium reduction and moderating protein consumption, should be discussed with your doctor.

End Stage Renal Disease (ESRD)

The options for a patient with ESRD are dialysis or a kidney transplant. Kidney transplantation has a very high success rate in people with Alport syndrome. Because Alport syndrome is a familial condition, related kidney donors must be carefully evaluated for this disease. Under most circumstances, any family member with a mutation in one of the type IV collagen chain genes should not be a kidney donor.

A condition called post-transplant anti-GBM (Glomerular Basement Membrane) nephritis occurs in an estimated 3-5% of transplanted Alport males.  It is an aggressive nephritis that often leads to failure of the transplant, so it is fortunate that it is an unusual problem.  Most (not all) of patients who develop anti-GBM nephritis after kidney transplant have an underlying diagnosis of Alport syndrome.

The majority of cases occur in males with X-linked Alport syndrome who reach ESRD before the age of 40 and who have sensorineural deafness.  The risk of post-transplant anti-GBM nephritis is very low in females with X-linked Alport syndrome, patients with detectable collagen IV alpha-5 chains in their skin or in their own kidneys, and in people who reach ESRD after age 40.  Post-transplant anti-GBM nephritis has occurred in women with Autosomal Recessive Alport syndrome. It could also occur in a male with Autosomal Recessive Alport syndrome.  It has not been reported in anyone with Autosomal Dominant Alport syndrome.

The diagnosis of post-transplant anti-GBM nephritis is made by transplant biopsy.  Alport patients can be screened for antibodies to GBM in the blood, but a negative test does not rule out post-transplant anti-GBM nephritis.  About 75% of cases of post-transplant anti-GBM nephritis occur in the first year after transplant.

Signs of post-transplant anti-GBM nephritis include hematuria, proteinuria and rising serum creatinine.  Alport patients who develop these abnormalities after transplant should be evaluated for post-transplant anti-GBM nephritis which includes a biopsy of the transplant.

Information on dialysis and transplantation can be found under the  Resources section of this website.

 

References that were used to compile this discussion include: Clifford E. Kashtan, MD – Alport syndrome and Thin Basement Membrane Nephropathy; Alport syndrome Treatments and Outcomes Registry (ASTOR); National Organization of Rare Diseases, Alport syndrome
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