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Expert Guidelines for the Management of AlportSyndrome and Thin Basement Membrane Nephropathy

Judy Savige,* Martin Gregory,† Oliver Gross,‡ Clifford Kashtan,§ Jie Ding,| and Frances Flinter¶

*Department of Medicine (Northern Health), University of Melbourne, Melbourne, Australia; †Division of Nephrology,University of Utah School of Medicine, Salt Lake City, Utah; ‡Department of Nephrology and Rheumatology, UniversityMedicine Goettingen, Goettingen, Germany; §Department of Pediatrics, University of Minnesota Medical School,Minneapolis, Minnesota; |Pediatric Department, Peking University First Hospital, Beijing, China; and ¶Department ofClinical Genetics, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom

ABSTRACTFew prospective, randomized controlled clinical trials address the diagnosis andmanagement of patients with Alport syndrome or thin basementmembrane nephrop-athy. Adult and pediatric nephrologists and geneticists from four continents whoseclinical practice focuses on these conditions have developed the following guidelines.The 18 recommendations are based on Level D (Expert opinion without explicit criticalappraisal, or based on physiology, bench research, or first principles—National HealthService category) or Level III (Opinions of respected authorities, based on clinicalexperience, descriptive studies, or reports of expert committees—U.S. PreventiveServices Task Force) evidence. The recommendations include the use of genetictesting as the gold standard for the diagnosis of Alport syndrome and the demonstra-tionof itsmodeof inheritance; theneed to identify and followall affectedmembersof afamily with X-linked Alport syndrome, including most mothers of affected males; thetreatment of males with X-linked Alport syndrome and individuals with autosomal re-cessive disease with renin-angiotensin system blockade, possibly even before the on-set of proteinuria; discouraging the affected mothers of males with X-linked Alportsyndrome from renal donation because of their own risk of kidney failure; and consid-erationofgenetic testing toexcludeX-linkedAlport syndrome in some individualswiththin basement membrane nephropathy. The authors recognize that as evidenceemerges, including data from patient registries, these guidelines will evolve further.

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Glomerular hematuria that persists for atleast a year occurs in at least 1% of thepopulation1–3 and is typically due to thinbasement membrane nephropathy(TBMN). Much less often, it results fromAlport syndrome.3–6 However, recognitionof Alport syndrome is more importantbecause of its inevitable progression toend-stage renal failure and the ability oftreatment to slow the rate of deterioration.

Alport syndrome is characterized byhematuria, renal failure, hearing loss, lenti-conus, and retinal flecks;7 a lamellated glo-merular basement membrane (GBM)8

with an abnormal collagen IV composi-tion;9 and mutations in the COL4A5 orCOL4A3/COL4A4 genes.10,11 Eighty-fivepercent of families have X-linked inheri-tance with mutations in COL4A5,12 andmost of the others have autosomal recessivedisease with homozygous or compoundheterozygous mutations in both copies (intrans) ofCOL4A3orCOL4A4.11Autosomaldominant inheritance is very rare andresults from heterozygous COL4A3 orCOL4A4 variants.13

Individuals with TBMN have isolatedhematuria.3 TBMN is usually caused by

heterozygous COL4A3 or COL4A4muta-tions and often represents the carrier stateof autosomal recessive Alport syndrome.3

Alport syndrome and TBMN may beclinically and ultrastructurally indistin-guishable, and some clinicians mistak-enly use the term TBMN in females andboys with X-linked Alport disease. Thedistinction between Alport syndromeand TBMN is, however, critical becauseof the different risks of renal failure andother complications for the individualand their family members.

Here we define Alport syndrome andTBMN, provide a diagnostic algorithmfor the patientwith persistent hematuria,describe the clinical features in Alportsyndromeandhow they contribute to thelikelihood of this diagnosis, list diseasesthat share clinical features with Alportsyndrome, and discuss criteria that helpdistinguish between X-linked and auto-somal recessive inheritance.

The following recommendations de-scribe the use of the terms “Alport syn-drome” and “TBMN” (recommendation1); criteria for the diagnosis of Alportsyndrome (recommendation 2); the

Published online ahead of print. Publication dateavailable at www.jasn.org.

Correspondence: Dr. Judy Savige, Department ofMedicine, The University of Melbourne, The North-ern Hospital, Epping, Victoria 3076, Australia. Email:jasavige@unimelb.edu.au

Copyright © 2013 by the American Society ofNephrology

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distinction between X-linked and auto-somal recessive inheritance (recommen-dation 3); how to predict the clinicalphenotype from the COL4A5 mutation(recommendation 4); the importance ofidentifying other affected family mem-bers (recommendation 5); the uses of ge-netic counseling (recommendation 6);ongoing medical management (recom-mendation 7); issues for the transplantrecipient (recommendation 8); and theaffected female: diagnosis, management,and the risks of renal donation (recom-mendation 9). The recommendationsalso address autosomal recessive Alportsyndrome: family screening (recommenda-tion 10), genetic counseling (recommenda-tion 11); management (recommendation12), and renal donation (recommenda-tion 13). The recommendations forTBMN include the criteria for diagnosis(recommendation 14), genetic testing(recommendation 15), management andprognostic indicators (recommendation16), family screening (recommendation17), and renal donation (recommenda-tion 18).

Prospective randomized controlledclinical trials for the diagnosis and man-agement of Alport syndrome and TBMNare difficult to undertake because of thesmall numbers of patients at individualtreatment centers and their differentstages of disease at presentation. Instead,our recommendations are largely basedon the experience and opinions of theauthors, aswell as retrospective studies inhumans, animal experiments, and anal-ysis of the Alport registries. The authorswere able to reach consensus on all therecommendations and considered thatthe benefits outweighed any potentialrisks. The authors were guarded only insuggesting the time to introduce renin-angiotensin system blockade in X-linkedAlport syndrome before formal evalua-tion in clinical trials. The evidence for allthe recommendations is presented in theintroductory comments to each section.

DEFINITIONS

The distinction between Alport syndromeand TBMN is critical but may be difficult

in females and boys with X-linked diseasewho have hematuria and GBM thinningbut not the characteristic hearing loss, lenti-conus, or retinopathy. The term “TBMN”should not be used in females or boyswith a thinned GBM due to X-linked Al-port syndrome. Their biopsy specimens, orthose of affected family members, usuallyshow a GBM with stretches of splitting orlamellation. Further clinical or genetic test-ing may be required. Clinicians shouldremember that inherited hematuria andrenal failure may be caused by TBMNwith coincidental renal disease.14

Recommendation 1The term “Alport syndrome” shouldbe reserved for patients with the char-acteristic clinical features and a lamel-lated GBM with an abnormal collagenIV composition, and in whom aCOL4A5 mutation (X-linked disease)or two COL4A3 or two COL4A4 muta-tions in trans (autosomal recessive dis-ease) are identified or expected. Theterm “thin basement membrane ne-phropathy” (TBMN) should be re-served for individuals with persistentisolated glomerular hematuria whohave a thinned GBM due to a hetero-zygous COL4A3 or COL4A4 (but notCOL4A5) mutation. TBMN shouldnot be used where there is a thinnedGBM and the diagnosis is likely to beX-linked Alport syndrome. This dis-tinction is to ensure patients whohave X-linked Alport syndrome arenot falsely reassured by the usually be-nign prognosis seen with TBMN. Al-port syndrome should not necessarilybe diagnosed where there is renal im-pairment together with a heterozygousCOL4A3 or COL4A4 mutation. This ismore likely to be due to TBMN, basedon its prevalence, together with a coin-cidental renal disease, such as IgA GN,or to autosomal recessive Alport syn-drome, with a second, undetectedmutation. In these circumstances, thecorrect diagnosis may require furtherdiscussions among the nephrologist,pathologist, clinical geneticist, oph-thalmologist, and audiologist, andinterpretation of the relevant testresults.

DIAGNOSIS OF ALPORTSYNDROME

Alport syndrome is suspected when thereis persistent glomerular hematuria. Thelikelihood increases with a family historyof Alport syndrome or renal failure, andno other obvious cause; or when thecharacteristic clinical features (hearingloss, lenticonus, or retinopathy) are pres-ent, or the GBM lacks the collagen IV a3,a4, and a5 chains (Figure 1). The diag-nosis is confirmed if there is a lamellatedGBM or a pathogenic mutation in theCOL4A5 gene or two pathogenicCOL4A3 or COL4A4mutations. The sen-sitivity and specificity of each of these fea-tures for X-linked Alport syndrome areprovided in Table 1.15 Genetic testingis at least 90% sensitive for X-linkeddisease.16

Alport syndrome must be distin-guished from the other causes of inheritedhematuria and renal failure, inheritedrenaldisease andhearing loss, retinalflecks,and GBM lamellation (Table 2). Hema-turia is not typical of the most commonfamilial forms of pediatric renal failure,namely FSGS and nephronophthisis.Hearing loss occurs with many differentinherited renal diseases but for other rea-sons. Other causes of GBM lamellationare very rare or have further distinctivehistological features.

Recommendation 2The diagnosis of Alport syndrome issuspected when an individual has glo-merular hematuria or renal failureand a family history of Alport syndromeor renal failure without another obviouscause. These individuals should undergotesting for microalbuminuria/protein-uria, as well as audiometry, an ophthal-mologic examination, and, preferably,renal biopsy for GBM ultrastructure,collagen IV composition, and an assess-ment of damage. The diagnosis of Alportsyndrome is highly likely if there are glo-merular hematuria and a family historyof Alport syndrome with no other causefor the hematuria ; if bilateral high-tonesensorineural hearing loss, lenticonus,or fleck retinopathy is present; or if theGBM lacks the collagen IVa5 chain. The

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diagnosis of Alport syndrome is con-firmed with the demonstration of alamellated GBM or a COL4A5 or twoCOL4A3 or COL4A4mutations. In indi-viduals in whom the diagnosis is still un-clear and genetic testing is not available,it is often useful to examine the child’smother or an older affectedmale relativeusing the same strategy.

MODES OF INHERITANCE

Once Alport syndrome has been diag-nosed, it is important to distinguishbetween X-linked and autosomal reces-sive inheritance because of the differentimplications, including the risk of renalfailure, for family members.

X-linkedAlport syndrome is five timesmore common than recessive disease.12

The mode of inheritance is sometimessuspected from the pedigree. With X-linked inheritance, disease appears toskip a generation, where there is an

affected female with hematuria and noother features.With recessive inheritance,disease typically occurs in a single gener-ation, males and females are affectedequally often and equally severely, andthe father of an affected individual mayhave hematuria. Recessive inheritance isalso suspected where a young female hasrenal failure, hearing loss, and ocular ab-normalities. Inheritance is usually con-firmed with genetic testing. Sometimesthe GBM collagen IV composition isused; however, this test is notwidely avail-able, and interpretation of the results maybe difficult in females with X-linked dis-ease.17 Features that distinguish X-linkedfrom autosomal recessive Alport syn-drome are summarized in Table 3.

Recommendation 3The mode of inheritance of Alport syn-drome is determined most accuratelywith the demonstration of a patho-genic mutation in the COL4A5 geneor two mutations in either the

COL4A3 or COL4A4 gene on differentchromosomes.

X-LINKED ALPORT SYNDROME

Most patients with X-linked Alport syn-dromehave another familymemberwithhematuria because only 15% mutationsoccur de novo and penetrance is 95%.18

Other X-linked causes of hematuria andrenal failure are very uncommon.

Males with X-linked Alport syndromewhodevelop end-stage renal failure beforeage 30 years usually have extrarenal man-ifestations,15,19 but those with late-onsetrenal failure may have only hearing loss(Table 3). The high-tone sensorineuralhearing loss occurs in 70% and lenticonusin up to 30% of affected males by thefourth decade, when renal failure, hear-ing loss, and retinopathy are alreadypresent. The central fleck (50%) and pe-ripheral coalescing (60%) retinopathiesare common. Females have variableclinical features depending on X chro-mosome inactivation in individual tis-sues, and their features are describedseparately.

GBM lamellation is usually wide-spread in men. The GBM is initiallythinned in boys, but there is focal lamel-lation20 that becomes more extensivewith time. The GBM collagen IV com-position is typically abnormal and lacksthe a3a4a5 network.9,21 The epidermalmembrane also has no a5 chain,22 andexamination of a skin biopsy specimen isless invasive and the results may be avail-able sooner than assessment of a renalbiopsy sample.22

Genetic TestingGenetic testing is useful when Alportsyndrome is suspected but cannot beconfirmed with other techniques andwhen TBMN is suspected but X-linkedAlport syndrome must be excluded (Ta-ble 4). Most ethical concerns related totesting children for Alport syndrome areoutweighed by the potential of treatmentto delay end-stage renal failure.23 Fur-ther information on molecular testingfor Alport syndrome is available atwww.genereviews.org (Table 5).

Figure 1. An approach to distinguish between Alport syndrome and thin basementmembrane nephropathy as the cause of persistent glomerular hematuria.

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The mutation detection rate in X-linked Alport syndrome is at least 90%with a combined approach of sequencinggenomic DNAor hair-root or skin cDNA,followed by multiplex ligation-dependentprobe amplification to detect large dele-tions, insertions, or duplications.24–28

Current techniques identify mainly cod-ing region variants. Mutations are morelikely to be identified in individuals withearly-onset renal failure and extrarenalfeatures,15,19,29 because the diagnosis of Al-port syndrome ismore likely to be accurate.

Mutations are different in each familywith X-linked Alport syndrome, andmorethan700variantshavebeendescribed(http://grenada.lumc.nl/LOVD2/COL4A/home.php?select_db=COL4A5).16 Clini-cal features depend mainly on the mu-tation’s location and genotype. About50% result in a stop codon either directlyor downstream, and 40% of mutationsare missense.16 Large deletions and rear-rangements, nonsense mutations, andcarboxy terminal missense mutationstypically result in early-onset renalfailure, hearing loss, and ocular abnor-malities,15,29 whereas amino terminalmissense mutations are often associatedwith late-onset renal failure without theextrarenal features. The likelihood of

early-onset renal failure in affected malescan also be predicted from the effect ofthe mutation in other affected malerelatives.29

Genetic linkage studies are used rarelyto exclude a mode of inheritance infamilies where no mutation has beendemonstrated,17 and, sometimes, in pre-natal or preimplantation genetic diagno-sis where the mutation is not known.30

Individuals with suspected Alport syn-drome but no COL4A5 mutation mayhave a deletion, splice site, or a deep in-tronic variant in COL4A5, autosomal re-cessive Alport syndrome, or, indeed,another inherited nephropathy.

Recommendation 4The demonstration of a pathogenicCOL4A5 variant confirms the diagno-sis of Alport syndrome and X-linkedinheritance. The mutation’s locationand nature help predict the likelihoodof early-onset renal failure and extra-renal features. These are sometimesalready obvious from the disease man-ifestations in other affected familymembers. The mutation itself or adisease-associated haplotype can beused in preimplantation and prenataldiagnosis.

Screening Members of a Family withX-Linked Alport SyndromeAll affected members of a family with X-linked Alport syndrome, including fe-males, should be identified because oftheir own risk, and their offspring’s risk,of renal failure. For any female withX-linked disease, each of her sons has a50% risk of being affected and develop-ing renal failure, and each of her daugh-ters has a 50% risk of being affected. Incontrast, a male with X-linked diseasecan be reassured that none of his sonswill inherit the mutation, but all of hisdaughters, and half of her sons anddaughters, will be affected. Thus, overall,the immediate risks are greater for theoffspring of an affected female thanfor a male with X-linked disease.

In any family with X-linked Alportsyndrome, individuals with hematuriaare highly likely to be affected, but othercoincidental causes of hematuriamust beexcluded. When the mutation in anyfamily is known, genetic testing can beused to confirm the affected status.

Recommendation 5All affected members of a family withX-linked Alport syndrome, includingfemales, should be identified. Most

Table 1. The diagnosis of X-linked Alport syndrome

Criteria Sensitivity Specificity Comments

Family history of Alportsyndrome

High (80%) High A positive history will be obvious immediately,or the family will need to spend time askingdistant family members. A family history may be absentwith de novo disease or where families are small, thereis no affected adult male, or disease is atypical.

Bilateral high-tone sensorineuralhearing loss

High Moderate Also occurs with aging, middle ear infections, and industrialnoise exposure. Hearing loss is also common in otherinherited renal diseases and with renal failureand dialysis.

Lenticonus Low to moderate (30%) Very high Only occurs in Alport syndrome. May be misdiagnosedas cataract.

Central fleck retinopathy Moderate (50%) Very high The perimacular flecks occur only in Alport syndromebut may be overlooked or misdiagnosed.

Lamellated GBM High Very high Typically generalized in affected adult males. Focal inboys and females but progresses with time.

a3a4a5(IV) collagen chainsabsent from GBM

Moderate (80% of malesand 60% females)

High May be focally absent in females.

a5(IV) collagen chain absentfrom skin

Moderate (80% of malesand 60% females)

High May be focally absent in females.

COL4A5 pathogenic variant High (.90%) High May be difficult to distinguish between pathogenic andnonpathogenic variants.

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mothers of affected boys are also af-fected. At-risk family members shouldbe screened for hematuria on at least 2occasions and offered other screeningtests, but genetic testing is preferred,especially if a mutation has alreadybeen identified in the family (cascadetesting).

Genetic CounselingGenetic counseling is usually appropriatewhere available.

Recommendation 6Affected individuals should be referredto an interested nephrologist for long-term management and offered a con-sultation with a clinical geneticist todiscuss the disease, its inheritance,and the indications for genetic testingof other family members. There shouldbe a non-directive discussion aboutavailable reproductive options, includ-ing prenatal and preimplantation ge-netic diagnosis, preferably prior to

any pregnancy. Individuals and theirfamilies should be advised of their di-agnosis, their risk of renal failure, andtheir children’s likelihood of inheritingthe causative mutation and developingrenal failure. Affected individualsshould be advised of the availabilityof local, national, and international pa-tient support groups and relevant web-sites (Table 5). They should also beencouraged to participate in patientregistries that will help improve under-standing of Alport syndrome and itsmanagement.

Monitoring and TreatmentProteinuria, hearing loss, lenticonus, ret-inopathy, and reduced levels of GBMcollagen IV a5 chain all correlate withan increased likelihood of early-onset re-nal failure in males,18,30,31 but the riskshave not been studied prospectively.Hearing continues to deteriorate inadulthood and is helped with hearingaids, but affected individuals shouldprotect their hearing from additionalinsults throughout life. The lenticonusalso worsens but can be corrected withlens replacement.32 The retinopathyprogresses but does not affect vision orrequire treatment.

Angiotensin-converting enzyme(ACE) inhibitors reduce proteinuria inchildren with X-linked Alport syn-drome.33 Angiotensin-receptor blockersand aldosterone inhibitors have addi-tional benefits for proteinuria.34 Evi-dence from a single retrospective study,animal models, and other forms of renalfailure suggest that ACE inhibitors delaythe onset of end-stage renal failure andimprove life expectancy in men, evenwhen begun before the onset of protein-uria.35 However, it is critical that theeffect of renin-angiotensin blockade onproteinuria and renal failure progressionis formally evaluated (EARLY PRO-TECTAlport study, EU Clinical Trials Regis-ter).36 In the meantime, one approach isto target individuals at greatest risk ofearly-onset renal failure.37 Other potentialtherapies include statins,38 metalloprotei-nase inhibitors,39 vasopeptidase inhibi-tors,40 chemokine receptor antagonists,41

and stem cell therapy.42,43

Table 2. Other causes of the characteristic features of Alport syndrome

Clinical Feature Causes

Persistent familial hematuria Glomerular hematuriaTBMNFamilial IgA diseaseMYH9-related disorders (Fechtner, Epstein syndromes)Membranoproliferative GN type 2 (dense deposit disease)Familial hemolytic uremic syndromeC3 nephropathy

Nonglomerular hematuriaAutosomal dominant polycystic kidney diseaseSickle cell disease or traitFamilial hypercalciuria, other familial forms of

urolithiasisRenal failure plus hearingloss

MYH9-related disorders (Fechtner syndrome)NephronophthisisBartter syndromeDistal renal tubular acidosisMELAS syndromeFabry diseaseBranchio-oto-renal syndromeTownes-Brock syndromeCHARGE syndromeKallmann syndromeAlstrom diseaseMuckle-Wells syndrome

Hearing loss Middle-ear infectionsAgeIndustrial noise exposureOtotoxic drugsRenal failure, dialysis

Retinal flecks Membranoproliferative GN type 2IgA disease, systemic lupus erythematosus, and some otherforms of GN

Severe hypertension (macular star)C3 nephropathy

Lamellated GBM Focal damageMYH9-related disorders (Fechtner, Epstein syndromes)Pierson syndromeNail-patella syndromeMutations in the tetraspanin (CD151) geneFrasier syndromeGalloway-Mowat syndrome

MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke; CHARGE, coloboma, heartanomalies, choanal atresia, retardation of growth and development, and genital and ear anomalies.

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Recommendation 7Males with X-linked Alport syndromeshould be managed lifelong by a ne-phrologist and have their risk factorsfor progressive renal failure optimized,including careful management of hy-pertension, proteinuria, and dyslipide-mia. Treatment with ACE inhibitors,even before the onset of proteinuria,especially in individuals with geneticmutations or a family history consis-tent with early-onset renal failure,may delay the onset of end-stage diseaseand improve life expectancy. Affected

individuals should avoid ototoxic med-ication and industrial noise exposure tominimize further hearing loss.

Renal TransplantationPatients with X-linked Alport syndromewho undergo transplantation have sur-vival rates and graft survival rates similarto or better than those of patients withother inherited renal diseases.44,45 Af-fected female family members should bestrongly discouraged fromdonating a kid-ney, but where this has occurred, both thedonor and the recipient should receive

nephroprotective treatment, such asrenin-angiotensin system blockade, fromthe time of surgery.

Three percent to 5% of males developanti-GBM disease with rapid allograftloss after transplantation.31,46,47 Anti-GBMdisease ismore commonwith largegene deletions48 but also occurs withother mutations.31 In these individuals,the risk of anti-GBM disease is higherafter subsequent renal transplants, andanti-GBM antibodies are best demon-strated with GBM immunohistochem-istry and less effectively with anti-GBMELISA because of different epitope spe-cificities.49

Recommendation 8Males with X-linked Alport syndromeand increased risk of anti-GBM diseasepost-transplant (early-onset renal fail-ure, extrarenal features) should bemonitored closely and undergo promptallograft biopsy for new-onset glomeru-lar hematuria, proteinuria, or renal im-pairment.

Table 3. Distinction between X-linked and autosomal recessive Alport syndrome

Characteristic X-linked Alport Syndrome Autosomal Recessive Alport Syndrome

Prevalence More common, occurs in 85% of all families 15% of all familiesSex Males are affected more often and more severely

than femalesMales and females affected with equal frequency

and severity; suspected where a female hasrenal failure, hearing loss, or ocular abnormalities

Age at first presentation Males have hematuria from infancy, but renal failureoccurs typically from the teenage years

Males and females present with hematuria frominfancy and develop renal failure in childhoodor adult life

Family history of renal failure Other male relatives may have renal failure; diseaseappears to “skip” a generation because affectedfemales are much less likely to develop renal failure

Renal failure typically found in only one generation.The exceptions are the rare families with multipleexamples of consanguinity

Carrier features 95% affected females have hematuria and 15%develop renal failure by the age of 60 years; hearingloss and peripheral retinopathy occur in nearly halfby age 60 yr

Carriers often have hematuria, but renal failureis uncommon, and hearing loss and ocularabnormalities do not occur

Pedigree analysis Mother typically has hematuria, and the father has nohematuria, that is, father-to-sondisease transmission does not occur

Hematuria but not renal failure may be presentin the mother and father and in other familymembers.

Lamellated GBM Yes, but thinning with focal lamellation in young boysand females becomes more lamellated with time

Yes

a3a4a5(IV) collagen chainsabsent from GBM

Yes Yes, but the a5(IV) chain persists in the Bowmancapsule and the distal tubular basementmembrane

a5(IV) collagen chain absentfrom skin

Yes No, the a5(IV) chain persists in the skin

Mutation analysis A single pathogenic mutation in the COL4A5 gene Two pathogenic mutations in the COL4A3 orCOL4A4 gene on different chromosomes

Table 4. Indications for genetic testing in Alport syndrome

To confirm the diagnosis of Alport syndromeTo identify the mode of inheritance (this indicates the risk of renal failure for other familymembers)

To exclude TBMN in individuals with persistent hematuriaTo help predict the risk of early-onset renal failure in X-linked disease based on DNA mutationcharacteristics or previously reported associations

To enable early prenatal diagnosis for females at risk of an affected pregnancyTo predict whether an embryo is affected prior to implantation (preimplantation geneticdiagnosis)

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X-linked Alport Syndrome inFemalesAlmost all (95%) females with X-linkedAlport syndrome have hematuria, andmany eventually develop other clinicalfeatures, especially proteinuria (75%),18

end-stage renal failure (8%–30%, overall15%, by the age of 60), hearing loss(40%), or peripheral retinopathy(40%).19,50 Lenticonus may not occur,and central retinopathy is rare. It istherefore debatable whether femalesshould be considered affected or carri-ers. Those who prefer the term “af-fected”maintain that it conveys the risksfor any female and the need for ongoingmonitoring and treatment.

Most (85%) mothers of affected boysalso have the mutation, but many areasymptomatic, and 80% are diagnosed

onlyafter theirsonoranothermalerelativehas presented. The GBM in affected fe-males is typically thinned with focal areasof lamellation that become more exten-sive with time.51 The collagen IV a3a4a5network is patchily present depending onX chromosome inactivation.

Renin-angiotensin system antago-nists are nephroprotective in femaleswith X-linked Alport syndrome andshould be used to treat those with hy-pertension, proteinuria, and other riskfactors for renal failure progression.52

Again preliminary support, but no evi-dence, suggests a beneficial effect for theinitiation of ACE inhibitor treatmenteven before the onset of proteinuria.35

Poor prognostic markers in females in-clude episodes of macroscopic hematu-ria in childhood and proteinuria.53–55 A

renal biopsy is warranted if there is sig-nificant proteinuria (for example, .1 g/din adults) or renal impairment. How-ever, changes in the renal biopsy speci-men and GBMmay be patchy, samplingvariation is common, and interpretationmay be difficult.56 Sometimes femaleswith X-linked Alport syndrome them-selves require a transplant for renal failure,but they do not subsequently developanti-GBM disease.30

A female family member commonlyconsiders donating one of her kidneys toan affected son or brother. The low denovo mutation rate means that mostmothers (85%) of affected males alsohave the mutation. A sister’s risk of hav-ing the mutation is 50% if her motheris a carrier. Carrier family members whoproceed with donation have an increased

Table 5. Relevant websites, including those for patient support groups

Web site Description

www.alportsyndrome.org This is the website of the US Alport Foundation. It is linked to the Alport Syndrome Treatmentsand Outcomes Registry (ASTOR) and has contact details for genetic testing laboratoriesworldwide and for kidney and skin immunohistochemistry in North America.

www.actionforalportscampaign.org United Kingdom–based patient support group that provides information for familiesaffected by Alport syndrome and brings together professionals with a particularinterest in the condition.

www.alportregistry.org ASTOR is a voluntary international patient registry established at the University ofMinnesota that aims to provide patients and families with the most current informationabout Alport syndrome. Information from this registry will be used to design futuretreatments.

www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=63&lng=EN

Alport Orphanet is a mainly European-centric site that describes the disease classifications;lists recent medical publications; links to other relevant websites; and gives contactdetails for expert treating centers, diagnostic testing laboratories, patient supportgroups, funding groups, research projects, clinical trials and registries, biobanks andnetworks.

www.arup.utah.edu/database/ALPORT/ALPORT_welcome.php

www.grenada.lumc.nl/LOVD2/COL4A/home.php?select_db=COL4A3

These curated COL4A5 mutation databases are hosted by the LOVD and ARUP Laboratories.

www.ncbi.nlm.nih.gov/books/NBK22183 This useful and comprehensive overview of Alport syndrome from NCBI provides specificgenetic information clearly described for each form of inheritance.

www.alport.de This is a voluntary international patient registry established at the University of Goettingen,Germany.

www.alport.de/EARLY PRO-TECT This website has information about the phase III, multicenter, randomized, double-blind,placebo-controlled trial to investigate the optimal timing of ACE inhibitor therapy andits safety in pediatric patients with early-stage disease.

ASTOR, Alport Syndrome Treatments and Outcomes Registry; LOVD, Leiden Open Variation Database; NCBI, National Center for Biomedical Information.

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risk of renal failure in later life, althoughthe extent of this increase is not known.Affected donors also have an increased riskof hypertension and microalbuminuria/proteinuria compared with other do-nors.57 A kidney biopsy is mandatoryin a mutation-carrying potential donor,even in those with normal renal functionand normal levels of proteinuria, to as-sess renal damage resulting from the ef-fects of random X inactivation.54 Femalecarriers should only be kidney donorsof last resort.58 Conversely, 15% of themothers of affected boys are not carriersand may donate a kidney to their sonwithout an increased risk of renal failure.They should still undergo renal biopsy toassess damage and, preferably, genetictesting to formally exclude the diagnosisof X-linked Alport syndrome.

The riskof preeclampsia is increased inaffected females with hypertension, pro-teinuria, or renal impairment, and preg-nancy may accelerate any decline in renalfunction already present.59 Preexistinghypertension and renal impairment pre-dict an increased risk of obstetric compli-cations,60 and proteinuria, hypertension,and renal impairment are all associatedwith preterm delivery.60

Recommendation 9Female carriers of X-linked Alport syn-drome typically have a good renal out-come, but, on average, 15% developend-stage renal failure by the age of60 years. Thus, the carrier state shouldbe viewed as at-risk rather than a be-nign condition. Clinicians should en-deavor to convey this information ina way that encourages regular follow-up examinations for signs of progres-sion, such as the development ofhypertension, proteinuria, or renal im-pairment, and for hearing loss, withoutengendering undue anxiety. Somewomen with hematuria want the diag-nosis of Alport syndrome confirmed orexcluded prior to making reproductivedecisions. This requires genetic testing.

Most mothers of an affected boy arecarriers andmay have clinical manifes-tations. Clinicians caring for an af-fected child should explain to themother the importance of ascertaining

her status and refer her to a clinicalgeneticist for predictive testing if thefamily’s mutation is known, and to anephrologist for clinical assessmentand management. Assessment in-cludes a renal biopsy if proteinuria orrenal impairment is present. Carrierfemales should be monitored carefullyand treated with renin-angiotensinblockade if they develop hypertension,microalbuminuria, or renal impair-ment. Carrier females should bestrongly discouraged from kidney do-nation because of their own increasedrisk of renal impairment and hyper-tension. Predonation kidney biopsy ismandatory to accurately determinethe extent of renal damage and furtherdiscourage donation if the damage issevere. If a female carrier proceedswith donation, she must be aware ofthe risks of developing renal failurein later life and should use nephropro-tective strategies to minimize the ef-fects of hypertension and proteinuriafrom the time of surgery. Fifteen per-cent of boys with X-linked Alport syn-drome are affected as the result of aspontaneous gene mutation and theirmothers are not carriers. These womenshould have disease excluded by test-ing for hematuria, and preferably bygenetic testing.

AUTOSOMAL RECESSIVE ALPORTSYNDROME

Clinical features in autosomal recessiveAlport syndrome are the same as formales with X-linked Alport syndrome.Autosomal recessive inheritance is sus-pected where disease is sporadic andoccurs in a single generation or a con-sanguineous family, where males andfemales in a family are affected withequal frequency and severity, where thefather also has hematuria, or where afemale has renal failure, hearing loss, orocular abnormalities. Autosomal reces-sive inheritance is confirmed when thereare two COL4A3 or two COL4A4 patho-genic mutations or the GBM lacks thecollagen IV a3, a4, and a5 chains butthe a5 chain persists in the Bowman

capsule and the distal tubular and theepidermal membrane.21,61

Genetic TestingGenetic testing is useful to confirm thediagnosis of autosomal recessive Alportsyndrome16 when it is suspected on thebasis of clinical features, family history,or renal immunohistochemistry. Fewermutations have been described for reces-sive than for X-linked disease, and toofew are known for genotype-phenotypecorrelations. Usually both the COL4A3and the COL4A4 genes are examined.Two mutations will be present in oneof these genes, and, where possible, thelaboratory should confirm that they af-fect different chromosomes by testingboth parents of the affected individual.Sometimes only one mutation is identi-fied and the other is presumed presentbut undetectable, consistent with auto-somal recessive, rather than the very rareautosomal dominant, inheritance.

Genetic CounselingIndividuals with autosomal recessiveAlport syndrome are typically from asingle generationwithin a family, but thesituation is more complicated wherethe family includes multiple examplesof consanguinity. The risk of the siblingof an individual with autosomal recessiveAlport syndrome also being affected is,on average, one in four. In general, eachparent of an individual with autosomalrecessive Alport syndrome is an obligatecarrier and will be heterozygous for oneof the causative mutations. Likewise,each offspring of an individual withautosomal recessive disease will also in-herit one of the causative mutations. Theparents and offspring have the samephenotype as TBMN with a low risk ofrenal failure.

Recommendation 10Individuals with autosomal recessiveAlport syndrome should be referredto an interested nephrologist forlong-term management and offeredthe opportunity to consult a clinicalgeneticist to discuss the disease, its in-heritance, and the risks for other familymembers. A nondirective discussion

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about the reproductive options, includ-ing prenatal and preimplantationgenetic diagnosis, should take place,preferably prior to any pregnancy. Indi-viduals and their families should be ad-vised of their diagnosis and risk of renalfailure and their children’s risk of inher-iting one or more of the mutationsand developing renal failure. Affectedindividuals should be advised of theavailability of local, national, and inter-national patient support groups andrelevant websites. They should also beencouraged to participate in registriesto help improve understanding of Al-port syndrome and its management.

Recommendation 11Parents, siblings, and offspring of theindividual with autosomal recessiveAlport syndrome should be tested forhematuria, proteinuria, and renal im-pairment and preferably undergo cas-cade testing for the causative mutations.Those with a heterozygous mutationshould be managed as for TBMN.

Monitoring and TreatmentEvidence from a small retrospective regis-try analysis suggests that renin-angiotensinsystem blockade, for example with ACEinhibitors, delays renal failure and im-proves life expectancy in individuals withautosomal recessive Alport syndrome andmay improve the outlook in carriers.35,52

Recommendation 12Individuals with autosomal recessiveAlport syndrome should be managedby a nephrologist and have their riskfactors for progressive renal failure op-timized, including hypertension, pro-teinuria, and dyslipidemia. Again,treatment with ACE inhibitors, fromthe time of diagnosis, even before theonset of proteinuria, may delay the on-set of renal failure and improve life ex-pectancy. Affected individuals shouldavoid ototoxic medication and indus-trial noise exposure to minimize fur-ther hearing loss.

Renal DonationIndividuals with only one of the muta-tions that contribute to autosomal

recessive Alport syndrome (parents, off-spring, some siblings) have a phenotypeidentical to that of TBMN. They canusually be kidney donors if a predonationrenal biopsy excludes significant renaldamage and genetic testing excludes X-linked Alport syndrome.3,62

Recommendation 13Individuals from families with auto-somal recessive Alport syndrome whohave only one of the causative muta-tions (parents, offspring, some sib-lings) may be renal donors if theyhave normal BP, proteinuria levels,and renal function; if coincidental re-nal disease has been excluded by renalbiopsy; and if X-linked Alport syn-drome has been excluded by genetictesting.

TBMN

TBMN affects 1% of the population andis characterized by hematuria, protein-uria (#200 mg/L), normal BP, normalrenal function, and a thinned GBM (Ta-ble 6).3 TBMN usually represents thecarrier state for autosomal recessive Al-port syndrome, and inheritance is auto-somal dominant. Typically the prognosisis good, but there is also an increased riskof hypertension, proteinuria, and renalimpairment.3 The risk of renal failure isincreased if there is coincidental renaldisease or diabetes.3 It remains impor-tant to exclude X-linked Alport syn-drome in these patients.3

DiagnosisTBMN is suspected clinically and a renalbiopsy is required onlywhere features areatypical. The most commonly usedmethod for the diagnosis of TBMN isthe demonstration of a thinned GBMwith awidth,250 nmor ameasurementspecific to a laboratory and adjusted forage and sex.63 This thinning involves atleast 50% of the GBM, without the la-mellation found in Alport syndrome.However, the Alport lamellation maybe patchy, and occasionally errors aremade in basing a diagnosis on GBM ap-pearance, especially in boys and females.

The demonstration of normal expres-sion of the collagen IV a3, a4, and a5chains in renal basement membranes inpatients whose clinical features are oth-erwise consistent with TBMN supportsthis diagnosis.64

Heterozygous COL4A3 and COL4A4mutations also cause autosomal domi-nant Alport syndrome.65 The diagnosisof autosomal dominant Alport syn-drome is reserved for individuals with alamellated GBMand autosomal dominantinheritance. Some reports of autosomaldominant Alport syndrome are likely torepresent TBMNwith a coincidental renaldisease, such as IgA GN.14 Errors inwhich the diagnosis is actually TBMNmean that family members will be mis-informed about their likelihood of renalfailure.

Recommendation 14TBMN is usually suspected clinicallywhere there is persistent glomerularhematuria, normal levels of proteinuria,and normal BP and renal function, with-out another obvious explanation. Theremay be a family history of hematuria,but not of Alport syndrome or renal fail-ure (except in families with autosomalrecessive Alport syndrome).

Individuals suspected of havingTBMN should undergo renal biopsy ifthey have atypical features (protein-uria in adults >1.0 g/d or renal impair-ment [estimated GFR, 90 ml/min per1.73 m2]), or if X-linked Alport syn-drome or a coincidental glomerularor tubulointerstitial abnormality can-not be excluded.

Genetic TestingTBMN is caused by a heterozygousmutation in the COL4A3 or COL4A4gene. Mutations are typically differentin each family, and testing both theCOL4A3 and the COL4A4 genes is usu-ally required. This is labor-intensive andexpensive, and it is usually more impor-tant in an individual with hematuriaonly to exclude a COL4A5 mutationand hence X-linked Alport syndrome,rather than to make a positive moleculardiagnosis of TBMN.

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Recommendation 15Genetic testing for COL4A3 andCOL4A4 mutations is not usually re-quired for the diagnosis of TBMN.Screening for COL4A5 mutations toexclude X-linked Alport syndrome isoften more important.

Monitoring and TreatmentThe prognosis of TBMNis usually good.3

However, some individuals develophypertension, proteinuria, or renal im-pairment, which are all risk factors forprogression to end-stage renal failure.Again, there is preliminary supportfrom a single retrospective study inhumans, a murine model of TBMN,and experience in other forms of diabeticand nondiabetic renal disease that renin-angiotensin blockade delays progressionto end-stage renal failure in at-risk indi-viduals.52,66–68

Recommendation 16Individuals with TBMN should beassessed at presentation for poor prog-nostic indicators (hypertension, pro-teinuria, renal impairment). Thosewith these features should be managedby a nephrologist, and treatmentshould include an ACE inhibitor to de-lay the onset of renal failure. Other in-dividuals with TBMNmay be reviewedevery 1–2 years for hypertension, pro-teinuria, and renal impairment bytheir primary care provider.

Genetic CounselingTBMNis inherited, but the penetrance ofhematuria is only 70%.3 The de novomutation rate is low, and almost all af-fected individuals have another familymember with the causative mutation,but not necessarily hematuria.3 On aver-age, half the children of an individualwith TBMN inherit the causative muta-tion but, because hematuria is incom-pletely penetrant, fewer have hematuria.The offspring of two parents withTBMN have a 25% risk of autosomal re-cessive Alport syndrome if both parentshave a mutation in the same COL4A3 orCOL4A4 gene.

Recommendation 17All individuals with TBMN and theirfamilies should be advised of the diag-nosis of TBMN, its inherited nature,and their low risk of renal failure.

Renal TransplantationThere havebeenmany reports of success-ful cadaveric renal transplants from do-nors with TBMN.3,62,69 The risk for livedonors with TBMN is less certain be-cause normal donors already have anincreased risk of hypertension and mi-croalbuminuria.

Recommendation 18Individuals with TBMNmay be kidneydonors if they have normal BP, pro-teinuria, and renal function, and if

genetic testing and renal biopsy haveexcluded X-linked Alport syndromeand coincidental renal disease. A renalbiopsy is mandatory prior to donationto assess renal damage. If an individualwith TBMN proceeds with renal dona-tion, he or she must be aware of therisks and use nephroprotective strate-gies to minimize the effects of hyper-tension and proteinuria from the timeof surgery.

PregnancyRisks are not usually increased duringpregnancy in women with TBMN if hy-pertension, proteinuria, and renal im-pairment are not present. Preeclampsia isnot more common.

CONCLUSIONS

There are still unresolved issues in thediagnosis and management of patientswith Alport syndrome and TBMN. Ran-domized controlled trials are expensive,and the results may take years. In thefuture, we are likely to rely more onregistries, in which patients undergosemi-standardized treatment and theirclinical progress isupdatedonline, some-times by the patients themselves. Inaddition, the mutation database initia-tives will help explain how mutations inautosomal recessive Alport syndromeand TBMN affect clinical features. In

Table 6. Diagnosis of TBMN

Characteristic Feature Sensitivity Specificity Comments

Persistent glomerular hematuria,minimal proteinuria, normal BP,and normal renal function

High (80%) Moderate TBMN is the most common cause; occurs in IgA diseasetoo but often with higher urinary red blood cell countsand (less commonly) proteinuria

Family history of hematuria Moderate (70%) High Family history of hematuria is also common in X-linkedAlport syndrome

Generally thinned GBM withoutfocal lamellation

95% High

Collagen IV a3a4a5 networkpresent in GBM

100% Moderate Supports but does not prove the diagnosis of TBMN

a5(IV) collagen chain present in skin Supports but does not prove the diagnosis of TBMNHematuria segregates withCOL4A3/COL4A4

40% High

Hematuria does not segregate withthe COL4A5 locus

High High Linkage studies require careful characterization of otherfamily members but are possible with very few members

Single mutation in COL4A3 or COL4A4 80% Very high

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the future, whole genome sequencing islikely to be the diagnostic test of choicebecause it examines all threeAlport genessimultaneously. In the meantime, diag-nostic laboratories must improve theirmethods to ensure detection of bothmutations in autosomal recessive disease.Otherwise, TBMN or autosomal dom-inant Alport syndrome is diagnosed,conditions in which the clinical impli-cations are very different.

ACKNOWLEDGMENTS

We would like to thank our patients with

Alport syndrome and Thin Basement Mem-

brane Nephropathy and their families.

C.K. has received honoraria from Athena

Diagnostics, and the Alport Syndrome Treat-

ments and Outcomes Registry is engaged in

collaborative research with the Novartis In-

stitute for Biomedical Research.

DISCLOSURESJ.S., M.G., O.G., J.D., and F.F. have no conflicts of

interest to declare.

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