Approach Considerations
No definite treatment exists for Alport syndrome. Research indicates that angiotensin-converting enzyme (ACE) inhibitors can reduce proteinuria and the progression of kidney disease. Thus, the use of ACE inhibitors is reasonable in patients with Alport syndrome who have proteinuria with or without hypertension; the same is true for angiotensin-receptor blockers (ARBs). Both classes of drugs apparently help to reduce proteinuria by decreasing intraglomerular pressure. Moreover, by inhibiting angiotensin II, a growth factor that is implicated in glomerular sclerosis, these drugs have a potential role in slowing sclerotic progression.
A small study by Daina and colleagues found that combination therapy with an ACE inhibitor, an ARB, a non-dihydropyridine calcium channel blocker, and a statin (benazepril, 10-20 mg/day;, valsartan, 80-160 mg/day; diltiazem, 60-120 mg/day; and fluvastatin, 40-80 mg/day), safely ameliorated albuminuria, hypertension, lipid abnormalities, and glomerular selectivity in Alport syndrome patients and halted long-term progression in those without kidney insufficiency. The 4-month study included nine albuminuric adults with Alport syndrome whose creatinine clearance was > 20 ml/min/1.73 m2. [24]
A multicenter, randomized, placebo-controlled, double-blind phase 3 trial of nephroprotective therapy with ramipril in children with Alport syndrome reported that ramipril decreased the risk of disease progression by almost half (hazard ratio 0.51 (0.12-2.20)). No safety issues (adverse event rate-ratio 1.00; 95% confidence interval 0.66-1.53) were reported. [25]
Some reports suggest that cyclosporine may reduce proteinuria and stabilize kidney function in patients with Alport syndrome; however, the studies were small and uncontrolled. Moreover, reports suggest that patient response to cyclosporine can vary and that the drug may accelerate the development of interstitial fibrosis due to calcineurin-induced nephrotoxicity. [26]
Kidney failure
Begin appropriate replacement therapy as kidney failure advances. Therapy includes the following:
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Erythropoietin for chronic anemia
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Phosphate binders and vitamin D to manage osteodystrophy
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Alkali to correct acidosis
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Antihypertensive therapy to control blood pressure
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Eventually, dialysis; hemodialysis or peritoneal dialysis does not raise specific problems
Pregnancy
In women with the more severe form of Alport syndrome, pregnancy may accelerate the progression to end-stage renal disease (ESRD).
Monitoring
Check 24-hour urinary protein, creatinine, and serum chemistry as follows:
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Annually in patients without renal insufficiency and in those with mild kidney insufficiency
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Every 6 months in patients with moderate kidney insufficiency
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Every 1-3 months in patients with advanced kidney failure
Kidney Transplantation
Kidney transplantation is usually offered to patients with Alport syndrome who develop ESRD. Recurrent disease does not occur in the transplanted kidney, and the allograft survival rate in these patients is similar to that in patients with other kidney diseases. [27, 4]
However, about 3-5% of male patients with transplants develop anti ̶ glomerular basement membrane (anti-GBM) nephritis. These individuals usually have earl- onset Alport syndrome with clinically significant hearing loss and ESRD by about age 20 years. Female patients with X-linked Alport syndrome (XLAS) and all patients with healthy hearing or late progression to ESRD have a low risk for anti-GBS nephritis.
In view of the excellent graft survival rates and very low incidence of anti-GBM disease, kidney transplantation is not contraindicated in patients with Alport syndrome. [27, 28]
Selection of living related donors for patients with Alport syndrome requires careful consideration of the risk for chronic kidney disease/ESRD on the basis of the genotype. Although molecular genetic analysis is not always possible, mutation identification is very helpful in making informed decisions about living kidney donation. [4]
Consultations
Consultations with the following clinicians may be necessary:
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Ophthalmologist
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Otorhinolaryngologist
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Transplant surgeon
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Surgeon
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Dialysis specialist
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Nephrologist
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Audiologist
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Genetic counselor
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Electron micrograph of a kidney biopsy from a patient with Alport syndrome. Note the splitting and lamellation of the glomerular basement membrane (see arrows).
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Electron micrograph from a patient with Alport syndrome revealing the typical splitting and splintering of the glomerular basement membrane (original magnification X3000). Courtesy of Glen S. Markowitz, MD, Department of Pathology, Columbia University College of Physicians and Surgeons, New York.
Tables
Alpha (IV) Chain |
Genes |
Chromosomal Location |
Mutation |
Alpha-1 (IV) |
COL4A1 |
13 |
Unknown |
Alpha-2 (IV) |
COL4A2 |
13 |
Unknown |
Alpha-3 (IV) |
COL4A3 |
2 |
ARASa |
Alpha-4 (IV) |
COL4A4 |
2 |
ARAS |
Alpha-5 (IV) |
COL4A5 |
X |
XLASb |
Alpha-6 (IV) |
COL4A6 |
X |
Leiomyomatosisc |
a Autosomal recessive Alport syndrome (mutations spanning 5' regions of COL4A5 and COL4A6 genes). b X-linked Alport syndrome. c Autosomal recessive Alport syndrome. |
|||
Alpha (IV) Chain |
Tissue Distribution |
Alpha-1 (IV) |
Ubiquitous |
Alpha-2 (IV) |
Ubiquitous |
Alpha-3 (IV) |
GBM, distal TBMa, Descemet membrane, Bruch membrane, anterior lens capsule, lungs, cochlea |
Alpha-4 (IV) |
GBM, distal TBM, Descemet membrane, Bruch membrane, anterior lens capsule, lungs, cochlea |
Alpha-5 (IV) |
GBM, distal TBM, Descemet membrane, Bruch membrane, anterior lens capsule, lungs, cochlea |
Alpha-6 (IV) |
Distal TBM, epidermal basement membrane |
a Tubular basement membrane. |
|
