2013年Alport综合征和薄基底膜肾病指南推荐

Recommendation 1
The term “Alport syndrome” should be reserved for patients with the characteristic clinical features and a lamellated GBM with an abnormal collagen IV composition, and in whom a COL4A5 mutation (X-linked disease) or two COL4A3 or two COL4A4 mutations in trans (autosomal recessive disease) are identified or expected. The term “thin basement membrane nephropathy” (TBMN) should be reserved for individuals with persistent isolated glomerular hematuria who have a thinned GBM due to a heterozygous COL4A3 or COL4A4 (but not COL4A5) mutation. TBMN should not be used where there is a thinned GBM and the diagnosis is likely to be X-linked Alport syndrome. This distinction is to ensure patients who have X-linked Alport syndrome are not falsely reassured by the usually benign prognosis seen with TBMN. Alport syndrome should not necessarily be diagnosed where there is renal impairment together with a heterozygous COL4A3 or COL4A4 mutation. This is more likely to be due to TBMN, based on its prevalence, together with a coincidental renal disease, such as IgA GN, or to autosomal recessive Alport syndrome, with a second, undetected mutation. In these circumstances, the correct diagnosis may require further discussions among the nephrologist, pathologist, clinical geneticist, ophthalmologist, and audiologist, and interpretation of the relevant test results.

Recommendation 2
The diagnosis of Alport syndrome is suspected when an individual has glomerular hematuria or renal failure and a family history of Alport syndrome or renal failure without another obvious cause. These individuals should undergo testing for microalbuminuria/proteinuria, as well as audiometry, an ophthalmologic examination, and, preferably,renal biopsy for GBM ultrastructure,collagen IV composition, and an assessment of damage. The diagnosis of Alport syndrome is highly likely if there are glomerular hematuria and a family history of Alport syndrome with no other cause for the hematuria ; if bilateral high-tone sensorineural hearing loss, lenticonus, or fleck retinopathy is present; or if the GBM lacks the collagen IV a5 chain. The diagnosis of Alport syndrome is confirmed with the demonstration of a lamellated GBM or a COL4A5 or two COL4A3 or COL4A4 mutations. In individuals in whom the diagnosis is still unclear and genetic testing is not available,it is often useful to examine the child’s mother or an older affected male relative using the same strategy.

Recommendation 3
The mode of inheritance of Alport syndrome is determined most accurately with the demonstration of a pathogenic mutation in the COL4A5 gene or two mutations in either the COL4A3 or COL4A4 gene on different chromosomes.

Recommendation 4
The demonstration of a pathogenic COL4A5 variant confirms the diagnosis of Alport syndrome and X-linked inheritance. The mutation’s location and nature help predict the likelihood of early-onset renal failure and extrarenal features. These are sometimes already obvious from the disease manifestations in other affected family members. The mutation itself or a disease-associated haplotype can be used in preimplantation and prenatal diagnosis.

Recommendation 5
All affected members of a family with X-linked Alport syndrome, including females, should be identified. Most mothers of affected boys are also affected. At-risk family members should be screened for hematuria on at least 2 occasions and offered other screening tests, but genetic testing is preferred,especially if a mutation has already been identified in the family (cascade testing).

Recommendation 6
Affected individuals should be referred to an interested nephrologist for long term management and offered a consultation with a clinical geneticist to discuss the disease, its inheritance,and the indications for genetic testing of other family members. There should be a non-directive discussion about available reproductive options, including prenatal and preimplantation genetic diagnosis, preferably prior to any pregnancy. Individuals and their families should be advised of their diagnosis, their risk of renal failure, and their children’s likelihood of inheriting the causative mutation and developing renal failure. Affected individuals should be advised of the availability of local, national, and international patient support groups and relevant websites (Table 5). They should also be encouraged to participate in patient registries that will help improve understanding of Alport syndrome and its management.

Recommendation 7
Males with X-linked Alport syndrome should be managed lifelong by a nephrologist and have their risk factors for progressive renal failure optimized,including careful management of hypertension, proteinuria, and dyslipidemia. Treatment with ACE inhibitors,even before the onset of proteinuria,especially in individuals with genetic mutations or a family history consistent with early-onset renal failure,may delay the onset of end-stage disease and improve life expectancy. Affected individuals should avoid ototoxic medication and industrial noise exposure to minimize further hearing loss.

Recommendation 8
Males with X-linked Alport syndrome and increased risk of anti-GBM disease post-transplant (early-onset renal failure, extrarenal features) should be monitored closely and undergo prompt allograft biopsy for new-onset glomerular hematuria, proteinuria, or renal impairment.

Recommendation 9
Female carriers of X-linked Alport syndrome typically have a good renal outcome, but, on average, 15% develop end-stage renal failure by the age of 60 years. Thus, the carrier state should be viewed as at-risk rather than a benign condition. Clinicians should endeavor to convey this information in a way that encourages regular followup examinations for signs of progression, such as the development of hypertension, proteinuria, or renal impairment, and for hearing loss, without engendering undue anxiety. Some women with hematuria want the diagnosis of Alport syndrome confirmed or excluded prior to making reproductive decisions. This requires genetic testing. Most mothers of an affected boy are carriers and may have clinical manifestations. Clinicians caring for an affected child should explain to the mother the importance of ascertaining her status and refer her to a clinical geneticist for predictive testing if the family’s mutation is known, and to a nephrologist for clinical assessment and management. Assessment includes a renal biopsy if proteinuria or renal impairment is present. Carrier females should be monitored carefully and treated with renin-angiotensin blockade if they develop hypertension, microalbuminuria, or renal impairment. Carrier females should be strongly discouraged from kidney donation because of their own increased risk of renal impairment and hypertension. Predonation kidney biopsy is mandatory to accurately determine the extent of renal damage and further discourage donation if the damage is severe. If a female carrier proceeds with donation, she must be aware of the risks of developing renal failure in later life and should use nephroprotective strategies to minimize the effects of hypertension and proteinuria from the time of surgery. Fifteen percent of boys with X-linked Alport syndrome are affected as the result of a spontaneous gene mutation and their mothers are not carriers. These women should have disease excluded by testing for hematuria, and preferably by genetic testing.

Recommendation 10
Individuals with autosomal recessive Alport syndrome should be referred to an interested nephrologist for long-term management and offered the opportunity to consult a clinical geneticist to discuss the disease, its inheritance, and the risks for other family members. A nondirective discussion about the reproductive options, including prenatal and preimplantation genetic diagnosis, should take place,preferably prior to any pregnancy. Individuals and their families should be advised of their diagnosis and risk of renal failure and their children’s risk of inheriting one or more of the mutations and developing renal failure. Affected individuals should be advised of the availability of local, national, and international patient support groups and relevant websites. They should also be encouraged to participate in registries to help improve understanding of Alport syndrome and its management.

Recommendation 11
Parents, siblings, and offspring of the individual with autosomal recessive Alport syndrome should be tested for hematuria, proteinuria, and renal impairment and preferably undergo cascade testing for the causative mutations.Those with a heterozygous mutation should be managed as for TBMN.

Recommendation 12
Individuals with autosomal recessive Alport syndrome should be managed by a nephrologist and have their risk factors for progressive renal failure optimized, including hypertension, proteinuria, and dyslipidemia. Again,treatment with ACE inhibitors, from the time of diagnosis, even before the onset of proteinuria, may delay the onset of renal failure and improve life expectancy. Affected individuals should avoid ototoxic medication and industrial noise exposure to minimize further hearing loss.

Recommendation 13
Individuals from families with autosomal recessive Alport syndrome who have only one of the causative mutations (parents, offspring, some siblings) may be renal donors if they have normal BP, proteinuria levels,and renal function; if coincidental renal disease has been excluded by renal biopsy; and if X-linked Alport syndrome has been excluded by genetic testing.

Recommendation 14
TBMN is usually suspected clinically where there is persistent glomerular hematuria, normal levels of proteinuria,and normal BP and renal function, without another obvious explanation. There may be a family history of hematuria,but not of Alport syndrome or renal failure (except in families with autosomal recessive Alport syndrome). Individuals suspected of having TBMN should undergo renal biopsy if they have atypical features (proteinuria in adults >1.0 g/d or renal impairment [estimated GFR<90 ml/min per 1.73 m2]), or if X-linked Alport syndrome or a coincidental glomerular or tubulointerstitial abnormality cannot be excluded.

Recommendation 15
Genetic testing for COL4A3 and COL4A4 mutations is not usually required for the diagnosis of TBMN.Screening for COL4A5 mutations to exclude X-linked Alport syndrome is often more important.

Recommendation 16
Individuals with TBMN should be assessed at presentation for poor prognostic indicators (hypertension, proteinuria, renal impairment). Those with these features should be managed by a nephrologist, and treatment should include an ACE inhibitor to delay the onset of renal failure. Other individuals with TBMN may be reviewed every 1–2 years for hypertension, proteinuria, and renal impairment by their primary care provider.

Recommendation 17
All individuals with TBMN and their families should be advised of the diagnosis of TBMN, its inherited nature,and their low risk of renal failure.

Recommendation 18
Individuals with TBMN may be kidney donors if they have normal BP, proteinuria, and renal function, and if genetic testing and renal biopsy have excluded X-linked Alport syndrome and coincidental renal disease. A renal biopsy is mandatory prior to donation to assess renal damage. If an individual with TBMN proceeds with renal donation, he or she must be aware of the risks and use nephroprotective strategies to minimize the effects of hypertension and proteinuria from the time of surgery.