Approach
Patients with X-linked, autosomal-recessive, autosomal-dominant or autosomal-digenic Alport syndrome (X-linked Alport syndrome [XLAS], autosomal-recessive Alport syndrome [ARAS], and Autosomal dominant Alport syndrome [ADAS], respectively) should be managed lifelong by a nephrologist with a focus on management of hypertension, proteinuria, and dyslipidemia. Treatment with an ACE inhibitor (and/or an angiotensin-II receptor antagonist) should be offered.[30][47] They should also be offered referral to a clinical geneticist.[5][23] Patients are commonly managed according to current local guidelines for hypertension, chronic kidney disease, and cardiovascular risk.[46][48] Monitoring for progression of renal disease is essential. Routine monitoring involves investigations for serum creatinine (for GFR abnormalities), fasting lipid panel, CBC, calcium/phosphate/PTH, uric acid, and urinalysis. Testing should be at least annually or more frequently as renal function declines.[46] Disease-specific controlled clinical trials in Alport nephropathy have been published, supporting evidence for ACE inhibitors delaying the onset of end-stage renal disease and improving survival.[30][47][49]
Although robust evidence for the use of specific agents in Alport syndrome from properly conducted clinical trials does not exist, consensus management guidelines have been published.[5][23][30][50]
Renal disease
Hypertension is secondary to the underlying renal disease. Frequent monitoring and early treatment are required to achieve a target based on current guidelines (i.e., <130/80 mmHg).
In adults, first-choice treatment for proteinuria with or without hypertension consists of an ACE inhibitor and/or an angiotensin-II receptor antagonist.
In children, treatment using blockade of the renin-angiotensin system to slow progression of renal disease is recommended:[30]
at the time of diagnosis (before the appearance of proteinuria) in males ages >12-24 months with XLAS and all patients (males and females) >12-24 months with ARAS
at the onset of microalbuminuria for females with XLAS and in all patients with ADAS.
The ACE inhibitor ramipril has been suggested as a first-line option in children, and either an angiotensin-II receptor antagonist (e.g., losartan) or an aldosterone antagonist (e.g., spironolactone) as a second-line option.[30][47][49]
Losartan has been found to be effective in reducing proteinuria in children with Alport syndrome with or without hypertension.[51]
In a 3-year open-label extension phase of this study, losartan and enalapril both maintained the reduction in proteinuria seen in the initial study although the sample size in each group was small and there was no placebo arm.[52]
Regular monitoring for adverse events such as orthostatic hypotension and hyperkalemia is recommended.
Progression to chronic kidney disease is due to the underlying nephropathy. Early referral to a nephrologist is required for consideration of renal replacement therapy, which may consist of transplantation or dialysis.
Transplant is the only cure for chronic kidney disease as it allows patients to stop dialysis. It can also reduce cardiovascular complications and therefore extend survival.
Overt posttransplant antiglomerular basement membrane (anti-GBM) disease occurs in a small percentage of Alport syndrome patients.[45][53][54] Onset is usually within the first year after transplantation but may occur years later. Regular screening for anti-GBM antibodies can be offered, especially if there is an underlying loss-of-function mutation and loss of alpha-5(IV) expression by immunohistochemistry. Graft loss is high and recurrence in second grafts is high. Patients with graft dysfunction (especially males with XLAS, and males and females with ADAS) should undergo renal allograft biopsy with direct immunofluorescence for IgG and C3 and be screened for circulating anti-GBM antibodies. Presentation of anti-GBM disease varies and ranges from asymptomatic increases in serum creatinine to gross hematuria, oliguria, and a rapidly progressive glomerulonephritis.
Where living related kidney donation is being considered, special consideration should be given to which family members may be considered as potential donors.[45][53] Initial screening for hematuria should be carried out to detect other affected or carrier members prior to extensive clinical evaluation. Genetic testing should ideally be used to guide donor selection. People who have been shown not to carry the familial mutation may be screened as potential donors. Few XLAS carrier females have been kidney donors.[55] Renal function may deteriorate in this group after donation but in exceptional circumstances donation may take place although the long-term prognosis remains unknown.[56]
Extrarenal disease
Sensorineural deafness
Hearing should be monitored by an audiologist from around ages 5 years in males with XLAS and all children with ARAS. Indications for earlier referral or referral of other patients with Alport syndrome include overt proteinuria, failure of hearing screen, speech delay or patient/family concern about hearing loss. The hearing loss can usually be managed with hearing aids. Patients should be educated about reducing the risk of noise-induced injury. The hearing loss does not improve with renal transplant.[3]
Visual disturbance
Children with lenticonus (bulging of the lens capsule and the underlying cortex) should be offered annual surveillance, although this does not need to be extended to adults, as the rate of complications is very low.[2][3] Cataracts may require surgical extraction (see Cataracts).
Diffuse leiomyomatosis
In cases of Alport syndrome with diffuse leiomyomatosis, surgery may also be required for any symptomatic leiomyomas.
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