Pediatrics

Alport syndrome

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Alport syndrome? What are the typical findings for this disease?

Alport syndrome is a hereditary glomerular disease that presents with sensorineural hearing loss, ocular defects, and progressive renal failure. The most common inheritance pattern is X-linked and affects male family members. Diagnosis is confirmed by renal biopsy demonstrating splitting of the lamina densa of the glomerular basement membrane. Although there is no cure for for Alport syndrome, antiproteinuric agents—angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)—are routinely used to reduce proteinuria in attempts to delay progression of renal disease. Dialysis and renal transplantation are available when end-stage renal disease (ESRD) develops.

Microscopic hematuria, mild proteinuria

Sensorineural hearing loss, ocular defects, family history of renal disease

Classic presentation of Alport syndrome

Males typically present with persistent microscopic hematuria with minimal to mild proteinuria during childhood. Over the years, hypertension, worsening proteinuria, and progressive renal insufficiency develop, until ESRD occurs around 16 to 35 years of age. The rate of hearing loss generally follows the progression of renal insufficiency. Fifteen to 20% of these patients will acquire anterior lenticonus.

Alport syndrome is also known as hereditary nephritis

The most common inheritance pattern is X-linked and affects only male family members. Females with X-linked Alport syndrome are carriers and may be asymptomatic or have mild renal involvement during their lifetime (microscopic hematuria, mild proteinuria, mild renal impairment, hypertension).

What other disease/condition shares some of these symptoms?

Thin basement membrane disease (benign familial hematuria)

IgA nephropathy

What caused this disease to develop at this time?

Alport syndrome is a hereditary disease with the onset of symptoms depending on the inheritance pattern (X-linked, autosomal recessive, autosomal dominant). Both the X-linked and autosomal recessive forms have similar clinical manifestations, with persistent microscopic hematuria in childhood; proteinuria, hypertension, and renal insufficiency developing over the years; and ultimately ESRD between the ages of 16 and 35 years. The rate of hearing loss generally follows the progression in renal insufficiency. Patients with the autosomal dominant form acquire renal insufficiency more slowly, with ESRD occurring at age 45-60 years. The onset of high-frequency hearing loss usually occurs at the same time as the onset of renal impairment. The onset of ocular findings is variable and so may not coincide with the onset of auditory and/or renal manifestations.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Diagnosis is by renal biopsy, which can detect type IV collagen alpha-3, alpha-4, and alpha-5 chains (COL4A3, COL4A4, COL4A5). Serum chemistry panels are used to monitor renal function. Serum chemistry panels, urine analysis, and first-morning urine protein-to-creatinine ratio should be obtained to monitor renal function.

If there is persistent proteinuria (urine protein-to-creatinine ratio greater than 0.2 or persistent renal insufficiency (elevated blood urea nitrogen and creatinine levels), a renal biopsy should be performed. Urinalysis is performed to evaluate for hematuria and/or proteinuria and a random urine protein to creatinine ratio can quantify any proteinuria (normal is <0.2).

Genetic testing is available and may aid in diagnosis. Prenatal testing is also available. Genetic Testing can be obtained at several international clinical laboratories by going to "GeneTests" sponsored by the National Center for Biotechnology information (NCBI)—http://www.ncbi.nlm.nih.gov/sites/GeneTests. In the United States, Athena Diagnostics in Worcester, Massachusetts offers genetic testing for Alport Syndrome— http://www.athenadiagnostics.com/content/index.jsp. Instructions on how to obtain the genetic tests are available at their website.

A skin biopsy may aid in diagnosis when the X-linked form is suspected (type IV collagen alpha-5-chain, COL4A5).

Would imaging studies be helpful? If so, which ones?

Renal ultrasonography may help rule out other renal pathologic conditions.

If you are able to confirm that the patient has Alport syndrome, what treatment should be initiated?

The patient should be referred to a pediatric nephrologist. If a pediatric nephrologist is not available, consider referring to an adult nephrologist. There is no cure for Alport syndrome. Therapy is aimed at delaying progression of renal disease.

If there is evidence of proteinuria (urine protein-to-creatinine ratio >0.2), using the combination of both an ACE inhibitor and an ARB results in a greater reduction in proteinuria than if either agentis used alone. One approach is to start with lisinopril (ACE inhibitor) at a starting dose of 0.07 mg/kg/day, then titrate by increasing the dose in increments of 2.5-5 mg to a medium dose of 20 mg daily. If proteinuria is still present, add losartan (an ARB) at a starting dose of 0.7 mg/kg/day. Increase losartan by increments of 12.5 mg. Make dose changes at weekly intervals and monitor for side effects of hyperkalemia and renal insufficiency (elevated blood urea nitrogen and creatinine levels) with each dose increase. Maximum dose of lisinopril is 80 mg daily and maximum dose of losartan is 100 mg daily. It is important to emphasize to the patient that maintaining adequate hydration is essential because volume depletion in the setting of taking an ACE inhibitor and an ARB may result in hyperkalemia and renal insufficiency.

If hypertension is present (defined as blood pressure at the 95th percentile based on age, sex, and height percentile), start amlodipine at 2.5 mg daily. Increase dose by 2.5 mg every 48-72 hours. Maximum dose of amlodipine is 10 mg daily. Target blood pressures below the 95th percentile. There is no cure for Alport syndrome. Therapy is aimed at delaying progression of renal disease. If the patient has proteinuria, an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker should be given. If the patient has hypertension, an antihypertensive agent should be given (ACE inhibitor, angiotensin receptor blocker, calcium channel blocker).

What are the adverse effects associated with each treatment option?

If the patient has renal insufficiency, the addition of an ACE inhibitor or angiotensin receptor blocker may decrease renal perfusion, resulting in worsening renal function.

What are the possible outcomes of this disease?

Prognosis is dependent on the inheritance pattern of Alport syndrome: X-linked, autosomal recessive (AR), or autosomal dominant (AD). The X-linked form is the most common and only males are severely affected. Microscopic hematuria typically presents in childhood. Hypertension, proteinuria, and hearing loss present during adolescence. The AR form has clinical manifestations and course similar to the X-linked form

Patients with the X-linked or AR form acquire end-stage renal disease (ESRD) between the ages of 16-35 years. Females with the X-linked form may be asymptomatic or have mild renal manifestations (microscopic hematuria, mild proteinuria, hypertension, mild renal insufficiency). Females and males are affected equally in the AR form. The AD form is the least common and tends to have slower progression of renal disease, with the development of ESRD at ages 45-60 years.

What causes this disease and how frequent is it?

There are three inheritance patterns of Alport syndrome: X-linked (80%), autosomal recessive (15%), autosomal dominant (5%) . The prevalence is 1 in 50,000 live births. Alport syndrome is due to defects in type IV collagen. The X-linked form results from mutations of COL4A5 on chromosome X. The autosomal recessive form results from mutations in COL4A3 or COL4A4 on chromosome 2. The autosomal dominant form also results from mutations in COL4A3 or COL4A4 on chromosome 2.

How do these pathogens/genes/exposures cause the disease?

Type IV collagen chains are located in the basement membranes of kidneys, cochlea, and eye. Defects in type IV collagen chains result in abnormally structured basement membranes in these organs.

What complications might you expect from the disease or treatment of the disease?

Progression of renal disease depends on the inheritance pattern. High-frequency hearing loss occurs at the same rate as the progression of renal disease. The onset of ocular abnormalities (anterior lenticonus, granulation of the retina, corneal erosion, posterior polymorphous dystrophy) is variable. Patients in whom ESRD develops will require dialysis and kidney transplantation.

How can this disease be prevented?

The disease cannot be prevented. Pharmacotherapy is targeted at delaying progression of renal disease. The patient should be referred to ophthalmologic and audiologic specialists annually. Genetic testing is available, and genetic counseling is highly recommended.

What is the evidence?

Review articles:

Kashtan, CE. "Alport syndrome. An inherited disorder of renal, ocular, and cochlear basement membranes". Medicine (Baltimore). vol. 78. 1999. pp. 338-60.

Kashtan, CE. "Alport syndrome and the X chromosome: implications of a diagnosis of Alport syndrome in females". Nephrol Dial Transplant. vol. 22. 2007. pp. 1499-505.

Kashtan, CE. "Renal transplantation in patients with Alport syndrome". Pediatr Transplant. vol. 10. 2006. pp. 651-7.

Kashtan, CE. "Familial hematurias: what we know nad what we don't". Pediatr Nephrol. vol. 20. 2005. pp. 1027-35.

Kashtan, CE, Pagon, RA, Bird, TD, Dolan, CR. "Collagen IV-related nephropathies (Alport syndrome and thin basement membrane nephropathy)". GeneReviewsTM. University of Washington, Seattle. 1993.

Clinical studies on therapies:

Webb, NJ, Lam, C, Shahinfar, S. "Efficacy and safety of losartan in children with Alport syndrome--results from a subgroup analysis of a prospective, randomized, placebo- or amlodipine-controlled trial". Nephrol Dial Transplant. vol. 26. 2011. pp. 2521-6.

Callís, L, Vila, A, Carrera, M, Nieto, J. "Long-term effects of cyclosporine A in Alport's syndrome". Kidney Int. vol. 55. 1999. pp. 1051-6.

Charbit, M, Gubler, MC, Dechaux, M. "Cyclosporin therapy in patients with Alport syndrome". Pediatr Nephrol. vol. 22. 2007. pp. 57-63.

Massella, L, Muda, AO, Legato, A. "Cyclosporine A treatment in patients with Alport syndrome: a single-center experience". Pediatr Nephrol. vol. 25. 2010. pp. 1269-75.

El-Husseini, A, El-Basuony, F, Mahmoud, I. "Long-term effects of cyclosporine in children with idiopathic nephrotic syndrome: a single-centre experience". Nephrol Dial Transplant. vol. 20. 2005. pp. 2433-8.

Proesmans, W, Van Dyck, M. "Enalapril in children with Alport syndrome". Pediatr Nephrol. vol. 19. 2004. pp. 271-5.

Useful websites:

http://www.aakp.org.

http://www.alportsyndrome.org.

Ongoing controversies regarding etiology, diagnosis, treatment

Cyclosporine therapy has been used to treat proteinuria in patients with Alport syndrome in Europe.These studies were uncontrolled with small patient numbers and demonstrated inconsistent results. Additional studies are needed to determine if immunosuppressive agents can delay the progression of renal disease in Alport syndrome.

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