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Expert Guidelines for the Management of Alport Syndrome and Thin 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, University Medicine Goettingen, Goettingen, Germany; §Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota; |Pediatric Department, Peking University First Hospital, Beijing, China; and ¶Department of Clinical Genetics, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom

ABSTRACT Few prospective, randomized controlled clinical trials address the diagnosis and heterozygous COL4A3 or COL4A4 muta- management of patients with Alport syndrome or thin basement membrane nephrop- tions and often represents the carrier state athy. Adult and pediatric nephrologists and geneticists from four continents whose of autosomal recessive Alport syndrome.3 clinical practice focuses on these conditions have developed the following guidelines. Alport syndrome and TBMN may be The 18 recommendations are based on Level D (Expert opinion without explicit critical clinically and ultrastructurally indistin- appraisal, or based on physiology, bench research, or first principles—National Health guishable, and some clinicians mistak- Service category) or Level III (Opinions of respected authorities, based on clinical enly use the term TBMN in females and experience, descriptive studies, or reports of expert committees—U.S. Preventive boys with X-linked Alport disease. The Services Task Force) evidence. The recommendations include the use of genetic distinction between Alport syndrome testing as the gold standard for the diagnosis of Alport syndrome and the demonstra- and TBMN is, however, critical because tion of its mode of inheritance; the need to identify and follow all affected members of a of the different risks of renal failure and family with X-linked Alport syndrome, including most mothers of affected males; the other complications for the individual treatment of males with X-linked Alport syndrome and individuals with autosomal re- and their family members. cessive disease with renin-angiotensin system blockade, possibly even before the on- Here we define Alport syndrome and set of ; discouraging the affected mothers of males with X-linked Alport TBMN, provide a diagnostic algorithm syndrome from renal donation because of their own risk of failure; and consid- for the patient with persistent , eration of genetic testing to exclude X-linked Alport syndrome in some individuals with describe the clinical features in Alport thin basement membrane nephropathy. The authors recognize that as evidence syndrome and how they contribute to the emerges, including data from patient registries, these guidelines will evolve further. likelihood of this diagnosis, list diseases that share clinical features with Alport J Am Soc Nephrol 24: 364–375, 2013. doi: 10.1681/ASN.2012020148 syndrome, and discuss criteria that help distinguish between X-linked and auto- somal recessive inheritance. Glomerular hematuria that persists for at with an abnormal IV composi- The following recommendations de- least a year occurs in at least 1% of the tion;9 and in the COL4A5 or scribe the use of the terms “Alport syn- population1–3 and is typically due to thin COL4A3/COL4A4 genes.10,11 Eighty-five drome” and “TBMN” (recommendation basement membrane nephropathy percent of families have X-linked inheri- 1); criteria for the diagnosis of Alport (TBMN).Muchlessoften,itresultsfrom tance with mutations in COL4A5,12 and syndrome (recommendation 2); the Alport syndrome.3–6 However, recognition mostoftheothershaveautosomalrecessive of Alport syndrome is more important disease with homozygous or compound in Published online ahead of print. Publication date because of its inevitable progression to heterozygous mutations in both copies ( available at www.jasn.org. end-stage renal failure and the ability of trans)ofCOL4A3 or COL4A4.11 Autosomal treatment to slow the rate of deterioration. dominant inheritance is very rare and Correspondence: Dr. Judy Savige, Department of COL4A3 Medicine, The University of Melbourne, The North- Alport syndrome is characterized by results from heterozygous or ern Hospital, Epping, Victoria 3076, Australia. Email: hematuria, renal failure, , lenti- COL4A4 variants.13 [email protected] fl 7 conus, and retinal ecks; alamellatedglo- Individuals with TBMN have isolated Copyright © 2013 by the American Society of merular basement membrane (GBM)8 hematuria.3 TBMN is usually caused by Nephrology

364 ISSN : 1046-6673/2403-364 J Am Soc Nephrol 24: 364–375, 2013 www.jasn.org SPECIAL ARTICLE distinction between X-linked and auto- in females and boys with X-linked disease DIAGNOSIS OF ALPORT somal recessive inheritance (recommen- who have hematuria and GBM thinning SYNDROME dation 3); how to predict the clinical but not the characteristic hearing loss, lenti- phenotype from the COL4A5 conus, or retinopathy. The term “TBMN” Alport syndrome is suspected when there (recommendation 4); the importance of should not be used in females or boys is persistent glomerular hematuria. The identifying other affected family mem- with a thinned GBM due to X-linked Al- likelihood increases with a family history bers (recommendation 5); the uses of ge- port syndrome. Their biopsy specimens, or of Alport syndrome or renal failure, and netic counseling (recommendation 6); those of affected family members, usually no other obvious cause; or when the ongoing medical management (recom- show a GBM with stretches of splitting or characteristic clinical features (hearing mendation 7); issues for the transplant lamellation. Further clinical or genetic test- loss, lenticonus, or retinopathy) are pres- recipient (recommendation 8); and the ing may be required. Clinicians should ent, or the GBM lacks the collagen IV a3, affected female: diagnosis, management, remember that inherited hematuria and a4, and a5 chains (Figure 1). The diag- and the risks of renal donation (recom- renal failure may be caused by TBMN nosis is confirmed if there is a lamellated mendation 9). The recommendations with coincidental renal disease.14 GBM or a pathogenic mutation in the also address autosomal recessive Alport COL4A5 gene or two pathogenic syndrome: family screening (recommenda- Recommendation 1 COL4A3 or COL4A4 mutations. The sen- tion 10), genetic counseling (recommenda- The term “Alport syndrome” should sitivity and specificity of each of these fea- tion 11); management (recommendation be reserved for patients with the char- tures for X-linked Alport syndrome are 12), and renal donation (recommenda- acteristic clinical features and a lamel- provided in Table 1.15 Genetic testing tion 13). The recommendations for lated GBM with an abnormal collagen is at least 90% sensitive for X-linked TBMN include the criteria for diagnosis IV composition, and in whom a disease.16 (recommendation 14), genetic testing COL4A5 mutation (X-linked disease) Alport syndrome must be distin- (recommendation 15), management and or two COL4A3 or two COL4A4 muta- guished from the other causes of inherited prognostic indicators (recommendation tions in trans (autosomal recessive dis- hematuria and renal failure, inherited 16), family screening (recommendation ease) are identified or expected. The renal disease and hearing loss, retinal flecks, 17), and renal donation (recommenda- term “thin basement membrane ne- and GBM lamellation (Table 2). Hema- tion 18). phropathy” (TBMN) should be re- turia is not typical of the most common Prospective randomized controlled served for individuals with persistent familial forms of pediatric renal failure, clinical trials for the diagnosis and man- isolated glomerular hematuria who namely FSGS and . agement of Alport syndrome and TBMN have a thinned GBM due to a hetero- Hearing loss occurs with many different are difficult to undertake because of the zygous COL4A3 or COL4A4 (but not inherited renal diseases but for other rea- small numbers of patients at individual COL4A5)mutation.TBMNshould sons. Other causes of GBM lamellation treatment centers and their different not be used where there is a thinned are very rare or have further distinctive stages of disease at presentation. Instead, GBM and the diagnosis is likely to be histological features. our recommendations are largely based X-linked Alport syndrome. This dis- on the experience and opinions of the tinction is to ensure patients who Recommendation 2 authors, as well as retrospective studies in have X-linked Alport syndrome are The diagnosis of Alport syndrome is humans, animal experiments, and anal- not falsely reassured by the usually be- suspected when an individual has glo- ysis of the Alport registries. The authors nign prognosis seen with TBMN. Al- merular hematuria or renal failure were able to reach consensus on all the port syndrome should not necessarily and a family history of Alport syndrome recommendations and considered that be diagnosed where there is renal im- or renal failure without another obvious the benefits outweighed any potential pairment together with a heterozygous cause. These individuals should undergo risks. The authors were guarded only in COL4A3 or COL4A4 mutation. This is testing for microalbuminuria/protein- suggesting the time to introduce renin- more likely to be due to TBMN, based uria,aswellasaudiometry,anophthal- angiotensin system blockade in X-linked on its prevalence, together with a coin- mologic examination, and, preferably, Alport syndrome before formal evalua- cidental renal disease, such as IgA GN, renal biopsy for GBM ultrastructure, tion in clinical trials. The evidence for all or to autosomal recessive Alport syn- collagen IV composition, and an assess- the recommendations is presented in the drome, with a second, undetected ment of damage. The diagnosis of Alport introductory comments to each section. mutation. In these circumstances, the syndrome is highly likely if there are glo- correct diagnosis may require further merular hematuria and a family history discussions among the nephrologist, of Alport syndrome with no other cause DEFINITIONS pathologist, clinical geneticist, oph- for the hematuria ; if bilateral high-tone thalmologist, and audiologist, and sensorineural hearing loss, lenticonus, The distinction between Alport syndrome interpretation of the relevant test or fleck retinopathy is present; or if the and TBMN is critical but may be difficult results. GBM lacks the collagen IV a5 chain. The

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COL4A3 or COL4A4 gene on different chromosomes.

X-LINKED ALPORT SYNDROME

Most patients with X-linked Alport syn- drome have another family member with hematuria because only 15% mutations occur de novo and penetrance is 95%.18 Other X-linked causes of hematuria and renal failure are very uncommon. Males with X-linked Alport syndrome who develop end-stage renal failure before age 30 years usually have extrarenal man- ifestations,15,19 but those with late-onset renal failure may have only hearing loss (Table 3). The high-tone sensorineural hearing loss occurs in 70% and lenticonus in up to 30% of affected males by the fourth decade, when renal failure, hear- ing loss, and retinopathy are already present. The central fleck (50%) and pe- ripheral coalescing (60%) retinopathies are common. Females have variable clinical features depending on X chro- Figure 1. An approach to distinguish between Alport syndrome and thin basement mosome inactivation in individual tis- membrane nephropathy as the cause of persistent glomerular hematuria. sues, and their features are described separately. GBM lamellation is usually wide- diagnosis of Alport syndrome is con- affected female with hematuria and no spread in men. The GBM is initially firmed with the demonstration of a other features. With recessive inheritance, thinned in boys, but there is focal lamel- lamellated GBM or a COL4A5 or two disease typically occurs in a single gener- lation20 that becomes more extensive COL4A3 or COL4A4 mutations. In indi- ation, males and females are affected with time. The GBM collagen IV com- vidualsinwhomthediagnosisisstillun- equally often and equally severely, and position is typically abnormal and lacks clear and genetic testing is not available, the father of an affected individual may the a3a4a5 network.9,21 The epidermal it is often useful to examine the child’s have hematuria. Recessive inheritance is membrane also has no a5chain,22 and mother or an older affected male relative also suspected where a young female has examination of a skin biopsy specimen is using the same strategy. renal failure, hearing loss, and ocular ab- less invasive and the results may be avail- normalities. Inheritance is usually con- able sooner than assessment of a renal firmed with genetic testing. Sometimes biopsy sample.22 MODES OF INHERITANCE the GBM collagen IV composition is used; however, this test is not widely avail- Genetic Testing Once Alport syndrome has been diag- able, and interpretation of the results may Genetic testing is useful when Alport nosed, it is important to distinguish be difficult in females with X-linked dis- syndrome is suspected but cannot be between X-linked and autosomal reces- ease.17 Features that distinguish X-linked confirmed with other techniques and sive inheritance because of the different from autosomal recessive Alport syn- when TBMN is suspected but X-linked implications, including the risk of renal drome are summarized in Table 3. Alport syndrome must be excluded (Ta- failure, for family members. ble 4). Most ethical concerns related to X-linked Alport syndrome is five times Recommendation 3 testing children for Alport syndrome are more common than recessive disease.12 The mode of inheritance of Alport syn- outweighed by the potential of treatment The mode of inheritance is sometimes drome is determined most accurately to delay end-stage renal failure.23 Fur- suspected from the pedigree. With X- with the demonstration of a patho- ther information on molecular testing linked inheritance, disease appears to genicmutationintheCOL4A5 gene for Alport syndrome is available at skip a generation, where there is an or two mutations in either the www.genereviews.org (Table 5).

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Table 1. The diagnosis of X-linked Alport syndrome Criteria Sensitivity Specificity Comments Family history of Alport High (80%) High A positive history will be obvious immediately, syndrome or the family will need to spend time asking distant family members. A family history may be absent with de novo disease or where families are small, there is no affected adult male, or disease is atypical. Bilateral high-tone sensorineural High Moderate Also occurs with aging, middle infections, and industrial hearing loss noise exposure. Hearing loss is also common in other inherited renal diseases and with renal failure and . Lenticonus Low to moderate (30%) Very high Only occurs in Alport syndrome. May be misdiagnosed as . Central fleck retinopathy Moderate (50%) Very high The perimacular flecks occur only in Alport syndrome but may be overlooked or misdiagnosed. Lamellated GBM High Very high Typically generalized in affected adult males. Focal in boys and females but progresses with time. a3a4a5(IV) collagen chains Moderate (80% of males High May be focally absent in females. absent from GBM and 60% females) a5(IV) collagen chain absent Moderate (80% of males High May be focally absent in females. from skin and 60% females) COL4A5 pathogenic variant High (.90%) High May be difficult to distinguish between pathogenic and nonpathogenic variants.

The mutation detection rate in X- early-onset renal failure in affected males Screening Members of a Family with linked Alport syndrome is at least 90% can also be predicted from the effect of X-Linked Alport Syndrome with a combined approach of sequencing themutationinotheraffectedmale All affected members of a family with X- genomic DNA or hair-root or skin cDNA, relatives.29 linked Alport syndrome, including fe- followed by multiplex ligation-dependent Genetic linkage studies are used rarely males, should be identified because of probe amplification to detect large dele- to exclude a mode of inheritance in their own risk, and their offspring’srisk, tions, insertions, or duplications.24–28 families where no mutation has been of renal failure. For any female with Current techniques identify mainly cod- demonstrated,17 and, sometimes, in pre- X-linked disease, each of her sons has a ing region variants. Mutations are more natal or preimplantation genetic diagno- 50% risk of being affected and develop- likely to be identified in individuals with sis where the mutation is not known.30 ing renal failure, and each of her daugh- early-onset renal failure and extrarenal Individuals with suspected Alport syn- ters has a 50% risk of being affected. In features,15,19,29 because the diagnosis of Al- drome but no COL4A5 mutation may contrast, a male with X-linked disease port syndrome is more likely to be accurate. have a deletion, splice site, or a deep in- can be reassured that none of his sons Mutations are different in each family tronic variant in COL4A5, autosomal re- will inherit the mutation, but all of his with X-linked Alport syndrome, and cessive Alport syndrome, or, indeed, daughters, and half of her sons and morethan 700 variants have been described another inherited nephropathy. daughters, will be affected. Thus, overall, (http://grenada.lumc.nl/LOVD2/COL4A/ the immediate risks are greater for the home.php?select_db=COL4A5).16 Clini- Recommendation 4 offspring of an affected female than cal features depend mainly on the mu- The demonstration of a pathogenic for a male with X-linked disease. tation’s location and genotype. About COL4A5 variant confirms the diagno- In any family with X-linked Alport 50% result in a stop codon either directly sis of Alport syndrome and X-linked syndrome, individuals with hematuria or downstream, and 40% of mutations inheritance. The mutation’s location are highly likely to be affected, but other are missense.16 Large deletions and rear- and nature help predict the likelihood coincidental causes of hematuria must be rangements, nonsense mutations, and of early-onset renal failure and extra- excluded. When the mutation in any carboxy terminal missense mutations renal features. These are sometimes family is known, genetic testing can be typically result in early-onset renal already obvious from the disease man- used to confirm the affected status. failure, hearing loss, and ocular abnor- ifestations in other affected family malities,15,29 whereas amino terminal members. The mutation itself or a Recommendation 5 missense mutations are often associated disease-associated haplotype can be All affected members of a family with with late-onset renal failure without the used in preimplantation and prenatal X-linked Alport syndrome, including extrarenal features. The likelihood of diagnosis. females, should be identified. Most

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Table 2. Other causes of the characteristic features of Alport syndrome any pregnancy. Individuals and their Clinical Feature Causes families should be advised of their di- Persistent familial hematuria Glomerular hematuria agnosis, their risk of renal failure, and ’ TBMN their children s likelihood of inheriting Familial IgA disease the causative mutation and developing MYH9-related disorders (Fechtner, Epstein syndromes) renal failure. Affected individuals Membranoproliferative GN type 2 (dense deposit disease) should be advised of the availability Familial hemolytic uremic syndrome of local, national, and international pa- C3 nephropathy tient support groups and relevant web- Nonglomerular hematuria sites (Table 5). They should also be Autosomal dominant polycystic encouraged to participate in patient Sickle cell disease or trait registries that will help improve under- Familial hypercalciuria, other familial forms of standing of Alport syndrome and its urolithiasis Renal failure plus hearing MYH9-related disorders (Fechtner syndrome) management. loss Nephronophthisis Bartter syndrome Monitoring and Treatment Distal renal tubular acidosis Proteinuria, hearing loss, lenticonus, ret- MELAS syndrome inopathy, and reduced levels of GBM collagen IV a5 chain all correlate with Branchio-oto-renal syndrome an increased likelihood of early-onset re- Townes-Brock syndrome nal failure in males,18,30,31 but the risks CHARGE syndrome have not been studied prospectively. Hearing continues to deteriorate in Alstrom disease adulthood and is helped with hearing Muckle-Wells syndrome Hearing loss Middle-ear infections aids, but affected individuals should Age protect their hearing from additional Industrial noise exposure insults throughout life. The lenticonus Ototoxic drugs also worsens but can be corrected with Renal failure, dialysis lens replacement.32 The retinopathy Retinal flecks Membranoproliferative GN type 2 progresses but does not affect vision or IgA disease, systemic lupus erythematosus, and some other require treatment. forms of GN Angiotensin-converting enzyme Severe hypertension (macular star) (ACE) inhibitors reduce proteinuria in C3 nephropathy children with X-linked Alport syn- Lamellated GBM Focal damage drome.33 Angiotensin-receptor blockers MYH9-related disorders (Fechtner, Epstein syndromes) Pierson syndrome and aldosterone inhibitors have addi- fi 34 Nail-patella syndrome tional bene ts for proteinuria. Evi- Mutations in the tetraspanin (CD151) gene dence from a single retrospective study, Frasier syndrome animal models, and other forms of renal Galloway-Mowat syndrome failure suggest that ACE inhibitors delay MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke; CHARGE, coloboma, heart the onset of end-stage renal failure and anomalies, choanal atresia, retardation of growth and development, and genital and ear anomalies. improve life expectancy in men, even when begun before the onset of protein- mothers of affected boys are also af- Recommendation 6 uria.35 However, it is critical that the fected. At-risk family members should Affected individuals should be referred effect of renin-angiotensin blockade on be screened for hematuria on at least 2 to an interested nephrologist for long- proteinuria and renal failure progression occasions and offered other screening term management and offered a con- is formally evaluated (EARLY PRO-TECT tests, but genetic testing is preferred, sultation with a clinical geneticist to Alport study, EU Clinical Trials Regis- especially if a mutation has already discuss the disease, its inheritance, ter).36 In the meantime, one approach is been identified in the family (cascade and the indications for genetic testing to target individuals at greatest risk of testing). of other family members. There should early-onset renal failure.37 Other potential be a non-directive discussion about therapies include statins,38 metalloprotei- Genetic Counseling available reproductive options, includ- nase inhibitors,39 vasopeptidase inhibi- Geneticcounseling is usually appropriate ing prenatal and preimplantation ge- tors,40 chemokine receptor antagonists,41 where available. netic diagnosis, preferably prior to and stem cell therapy.42,43

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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 families Sex Males are affected more often and more severely Males and females affected with equal frequency than females and severity; suspected where a female has renal failure, hearing loss, or ocular abnormalities Age at first presentation Males have hematuria from infancy, but renal failure Males and females present with hematuria from occurs typically from the teenage years infancy and develop renal failure in childhood or adult life Family history of renal failure Other male relatives may have renal failure; disease Renal failure typically found in only one generation. appears to “skip” a generation because affected The exceptions are the rare families with multiple females are much less likely to develop renal failure examples of consanguinity Carrier features 95% affected females have hematuria and 15% Carriers often have hematuria, but renal failure develop renal failure by the age of 60 years; hearing is uncommon, and hearing loss and ocular loss and peripheral retinopathy occur in nearly half abnormalities do not occur by age 60 yr Pedigree analysis Mother typically has hematuria, and the father has no Hematuria but not renal failure may be present hematuria, that is, father-to-son in the mother and father and in other family disease transmission does not occur members. Lamellated GBM Yes, but thinning with focal lamellation in young boys Yes and females becomes more lamellated with time a3a4a5(IV) collagen chains Yes Yes, but the a5(IV) chain persists in the Bowman absent from GBM capsule and the distal tubular basement membrane a5(IV) collagen chain absent Yes No, the a5(IV) chain persists in the skin from skin Mutation analysis A single pathogenic mutation in the COL4A5 gene Two pathogenic mutations in the COL4A3 or COL4A4 gene on different chromosomes

Table 4. Indications for genetic testing in Alport syndrome nephroprotective treatment, such as To confirm the diagnosis of Alport syndrome renin-angiotensin system blockade, from To identify the mode of inheritance (this indicates the risk of renal failure for other family the time of surgery. members) Three percent to 5% of males develop To exclude TBMN in individuals with persistent hematuria anti-GBM disease with rapid allograft To help predict the risk of early-onset renal failure in X-linked disease based on DNA mutation loss after transplantation.31,46,47 Anti- characteristics or previously reported associations GBM disease is more common with large To enable early prenatal diagnosis for females at risk of an affected pregnancy gene deletions48 but also occurs with To predict whether an embryo is affected prior to implantation (preimplantation genetic other mutations.31 In these individuals, diagnosis) the risk of anti-GBM disease is higher after subsequent renal transplants, and anti-GBM antibodies are best demon- Recommendation 7 individuals should avoid ototoxic med- strated with GBM immunohistochem- Males with X-linked Alport syndrome ication and industrial noise exposure to istry and less effectively with anti-GBM should be managed lifelong by a ne- minimize further hearing loss. ELISA because of different epitope spe- phrologist and have their risk factors cificities.49 for progressive renal failure optimized, Renal Transplantation including careful management of hy- Patients with X-linked Alport syndrome Recommendation 8 pertension, proteinuria, and dyslipide- who undergo transplantation have sur- Males with X-linked Alport syndrome mia. Treatment with ACE inhibitors, vival rates and graft survival rates similar and increased risk of anti-GBM disease even before the onset of proteinuria, to or better than those of patients with post-transplant (early-onset renal fail- especially in individuals with genetic other inherited renal diseases.44,45 Af- ure, extrarenal features) should be mutations or a family history consis- fected female family members should be monitored closely and undergo prompt tent with early-onset renal failure, strongly discouraged from donating a kid- allograft biopsy for new-onset glomeru- may delay the onset of end-stage disease ney, but where this has occurred, both the lar hematuria, proteinuria, or renal im- and improve life expectancy. Affected donor and the recipient should receive pairment.

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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 Treatments and Outcomes Registry (ASTOR) and has contact details for genetic testing laboratories worldwide and for kidney and skin immunohistochemistry in North America. www.actionforalportscampaign.org United Kingdom–based patient support group that provides information for families affected by Alport syndrome and brings together professionals with a particular interest in the condition. www.alportregistry.org ASTOR is a voluntary international patient registry established at the University of Minnesota that aims to provide patients and families with the most current information about Alport syndrome. Information from this registry will be used to design future treatments. www.orpha.net/consor/cgi-bin/ Alport Orphanet is a mainly European-centric site that describes the disease classifications; OC_Exp.php?Expert=63&lng=EN lists recent medical publications; links to other relevant websites; and gives contact details for expert treating centers, diagnostic testing laboratories, patient support groups, funding groups, research projects, clinical trials and registries, biobanks and networks. www.arup.utah.edu/database/ALPORT/ These curated COL4A5 mutation databases are hosted by the LOVD and ARUP Laboratories. ALPORT_welcome.php www.grenada.lumc.nl/LOVD2/COL4A/ home.php?select_db=COL4A3 www.ncbi.nlm.nih.gov/books/NBK22183 This useful and comprehensive overview of Alport syndrome from NCBI provides specific genetic 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 and its 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.

X-linked Alport Syndrome in onlyaftertheirsonoranothermalerelative renal biopsy is warranted if there is sig- Females has presented. The GBM in affected fe- nificant proteinuria (for example, .1g/d Almost all (95%) females with X-linked males is typically thinned with focal areas in adults) or renal impairment. How- Alport syndrome have hematuria, and of lamellation that become more exten- ever, changes in the renal biopsy speci- many eventually develop other clinical sive with time.51 The collagen IV a3a4a5 men and GBM may be patchy, sampling features, especially proteinuria (75%),18 network is patchily present depending on variation is common, and interpretation end-stage renal failure (8%–30%, overall inactivation. may be difficult.56 Sometimes females 15%, by the age of 60), hearing loss Renin-angiotensin system antago- with X-linked Alport syndrome them- (40%), or peripheral retinopathy nists are nephroprotective in females selves require a transplant for renal failure, (40%).19,50 Lenticonus may not occur, with X-linked Alport syndrome and but they do not subsequently develop and central retinopathy is rare. It is should be used to treat those with hy- anti-GBM disease.30 therefore debatable whether females pertension, proteinuria, and other risk A female family member commonly should be considered affected or carri- factors for renal failure progression.52 considers donating one of her kidneys to ers. Those who prefer the term “af- Again preliminary support, but no evi- an affected son or brother. The low de fected” maintain that it conveys the risks dence, suggests a beneficial effect for the novo mutation rate means that most for any female and the need for ongoing initiation of ACE inhibitor treatment mothers (85%) of affected males also monitoring and treatment. even before the onset of proteinuria.35 have the mutation. A sister’s risk of hav- Most (85%) mothers of affected boys Poor prognostic markers in females in- ing the mutation is 50% if her mother also have the mutation, but many are clude episodes of macroscopic hematu- is a carrier. Carrier family members who asymptomatic, and 80% are diagnosed ria in childhood and proteinuria.53–55 A proceed with donation have an increased

370 Journal of the American Society of Nephrology J Am Soc Nephrol 24: 364–375, 2013 www.jasn.org SPECIAL ARTICLE risk of renal failure in later life, although her status and refer her to a clinical capsule and the distal tubular and the the extent of this increase is not known. geneticist for predictive testing if the epidermal membrane.21,61 Affected donors also have an increased risk family’s mutation is known, and to a of hypertension and microalbuminuria/ nephrologist for clinical assessment Genetic Testing proteinuria compared with other do- and management. Assessment in- Genetic testing is useful to confirm the nors.57 A kidney biopsy is mandatory cludes a renal biopsy if proteinuria or diagnosis of autosomal recessive Alport in a mutation-carrying potential donor, renal impairment is present. Carrier syndrome16 when it is suspected on the even in those with normal renal function females should be monitored carefully basis of clinical features, family history, and normal levels of proteinuria, to as- and treated with renin-angiotensin or renal immunohistochemistry. Fewer sess renal damage resulting from the ef- blockade if they develop hypertension, mutations have been described for reces- fects of random X inactivation.54 Female microalbuminuria, or renal impair- sive than for X-linked disease, and too carriers should only be kidney donors ment. Carrier females should be few are known for genotype-phenotype of last resort.58 Conversely, 15% of the strongly discouraged from kidney do- correlations. Usually both the COL4A3 mothers of affected boys are not carriers nation because of their own increased and the COL4A4 genes are examined. and may donate a kidney to their son risk of renal impairment and hyper- Two mutations will be present in one without an increased risk of renal failure. tension. Predonation kidney biopsy is of these genes, and, where possible, the They should still undergo renal biopsy to mandatory to accurately determine laboratory should confirm that they af- assess damage and, preferably, genetic the extent of renal damage and further fect different chromosomes by testing testing to formally exclude the diagnosis discourage donation if the damage is both parents of the affected individual. of X-linked Alport syndrome. severe. If a female carrier proceeds Sometimes only one mutation is identi- The risk of preeclampsia is increased in with donation, she must be aware of fied and the other is presumed present affected females with hypertension, pro- the risks of developing renal failure but undetectable, consistent with auto- teinuria, or renal impairment, and preg- in later life and should use nephropro- somal recessive, rather than the very rare nancy may accelerate any decline in renal tective strategies to minimize the ef- autosomal dominant, inheritance. function already present.59 Preexisting fects of hypertension and proteinuria hypertension and renal impairment pre- from the time of surgery. Fifteen per- Genetic Counseling dict an increased risk of obstetric compli- cent of boys with X-linked Alport syn- Individuals with autosomal recessive cations,60 and proteinuria, hypertension, dromeareaffectedastheresultofa Alport syndrome are typically from a and renal impairment are all associated spontaneous gene mutation and their single generation within a family, but the with preterm delivery.60 mothers are not carriers. These women situation is more complicated where should have disease excluded by test- the family includes multiple examples Recommendation 9 ing for hematuria, and preferably by of consanguinity. The risk of the sibling Female carriers of X-linked Alport syn- genetic testing. of an individual with autosomal recessive drome typically have a good renal out- Alport syndrome also being affected is, come, but, on average, 15% develop on average, one in four. In general, each end-stage renal failure by the age of AUTOSOMAL RECESSIVE ALPORT parent of an individual with autosomal 60 years. Thus, the carrier state should SYNDROME recessive Alport syndrome is an obligate be viewed as at-risk rather than a be- carrier and will be heterozygous for one nign condition. Clinicians should en- Clinical features in autosomal recessive of the causative mutations. Likewise, deavor to convey this information in Alport syndrome are the same as for each offspring of an individual with a way that encourages regular follow- males with X-linked Alport syndrome. autosomal recessive disease will also in- up examinations for signs of progres- Autosomal recessive inheritance is sus- herit one of the causative mutations. The sion,suchasthedevelopmentof pected where disease is sporadic and parents and offspring have the same hypertension, proteinuria, or renal im- occurs in a single generation or a con- phenotype as TBMN with a low risk of pairment, and for hearing loss, without sanguineous family, where males and renal failure. engendering undue anxiety. Some females in a family are affected with women with hematuria want the diag- equal frequency and severity, where the Recommendation 10 nosis of Alport syndrome confirmed or father also has hematuria, or where a Individuals with autosomal recessive excluded prior to making reproductive female has renal failure, hearing loss, or Alport syndrome should be referred decisions. This requires genetic testing. ocular abnormalities. Autosomal reces- to an interested nephrologist for Most mothers of an affected boy are sive inheritance is confirmed when there long-term management and offered carriers and may have clinical manifes- are two COL4A3 or two COL4A4 patho- the opportunity to consult a clinical tations. Clinicians caring for an af- genic mutations or the GBM lacks the geneticist to discuss the disease, its in- fected child should explain to the collagen IV a3, a4, and a5chainsbut heritance, and the risks for other family mother the importance of ascertaining the a5 chain persists in the Bowman members. A nondirective discussion

J Am Soc Nephrol 24: 364–375, 2013 Alport Syndrome and TBMN 371 SPECIAL ARTICLE www.jasn.org about the reproductive options, includ- recessive Alport syndrome (parents, off- The demonstration of normal expres- ing prenatal and preimplantation spring, some siblings) have a phenotype sion of the collagen IV a3, a4, and a5 genetic diagnosis, should take place, identical to that of TBMN. They can chains in renal basement membranes in preferably prior to any pregnancy. Indi- usually be kidney donors if a predonation patients whose clinical features are oth- viduals and their families should be ad- renal biopsy excludes significant renal erwise consistent with TBMN supports vised of their diagnosis and risk of renal damage and genetic testing excludes X- this diagnosis.64 failure and their children’sriskofinher- linked Alport syndrome.3,62 Heterozygous COL4A3 and COL4A4 iting one or more of the mutations mutations also cause autosomal domi- and developing renal failure. Affected Recommendation 13 nant Alport syndrome.65 The diagnosis individuals should be advised of the Individuals from families with auto- of autosomal dominant Alport syn- availability of local, national, and inter- somal recessive Alport syndrome who drome is reserved for individuals with a national patient support groups and have only one of the causative muta- lamellated GBM and autosomal dominant relevant websites. They should also be tions (parents, offspring, some sib- inheritance. Some reports of autosomal encouraged to participate in registries lings) may be renal donors if they dominant Alport syndrome are likely to to help improve understanding of Al- have normal BP, proteinuria levels, represent TBMN with a coincidental renal port syndrome and its management. and renal function; if coincidental re- disease, such as IgA GN.14 Errors in nal disease has been excluded by renal which the diagnosis is actually TBMN Recommendation 11 biopsy; and if X-linked Alport syn- mean that family members will be mis- Parents, siblings, and offspring of the drome has been excluded by genetic informed about their likelihood of renal individual with autosomal recessive testing. failure. Alport syndrome should be tested for hematuria, proteinuria, and renal im- Recommendation 14 pairment and preferably undergo cas- TBMN TBMN is usually suspected clinically cade testing for the causative mutations. where there is persistent glomerular Those with a heterozygous mutation TBMN affects 1% of the population and hematuria, normal levels of proteinuria, should be managed as for TBMN. is characterized by hematuria, protein- and normal BP and renal function, with- uria (#200 mg/L), normal BP, normal out another obvious explanation. There Monitoring and Treatment renal function, and a thinned GBM (Ta- may be a family history of hematuria, Evidence from a small retrospective regis- ble 6).3 TBMN usually represents the but not of Alport syndrome or renal fail- try analysis suggests that renin-angiotensin carrier state for autosomal recessive Al- ure (except in families with autosomal system blockade, for example with ACE port syndrome, and inheritance is auto- recessive Alport syndrome). inhibitors, delays renal failure and im- somal dominant. Typically the prognosis Individuals suspected of having proves life expectancy in individuals with is good, but there is also an increased risk TBMN should undergo renal biopsy if autosomal recessive Alport syndrome and of hypertension, proteinuria, and renal they have atypical features (protein- may improve the outlook in carriers.35,52 impairment.3 The risk of renal failure is uria in adults >1.0 g/d or renal impair- increased if there is coincidental renal ment [estimated GFR , 90 ml/min per Recommendation 12 disease or diabetes.3 It remains impor- 1.73 m2]), or if X-linked Alport syn- Individuals with autosomal recessive tant to exclude X-linked Alport syn- drome or a coincidental glomerular Alport syndrome should be managed drome in these patients.3 or tubulointerstitial abnormality can- by a nephrologist and have their risk not be excluded. factors for progressive renal failure op- Diagnosis timized, including hypertension, pro- TBMN is suspected clinically and a renal teinuria, and . Again, biopsy is required only where features are Genetic Testing treatment with ACE inhibitors, from atypical. The most commonly used TBMN is caused by a heterozygous the time of diagnosis, even before the method for the diagnosis of TBMN is mutation in the COL4A3 or COL4A4 onset of proteinuria, may delay the on- the demonstration of a thinned GBM gene. Mutations are typically different set of renal failure and improve life ex- with awidth ,250 nm or a measurement in each family, and testing both the pectancy. Affected individuals should specific to a laboratory and adjusted for COL4A3 and the COL4A4 genesisusu- avoid ototoxic medication and indus- age and sex.63 This thinning involves at ally required. This is labor-intensive and trial noise exposure to minimize fur- least 50% of the GBM, without the la- expensive, and it is usually more impor- ther hearing loss. mellation found in Alport syndrome. tant in an individual with hematuria However, the Alport lamellation may only to exclude a COL4A5 mutation Renal Donation be patchy, and occasionally errors are and hence X-linked Alport syndrome, Individuals with only one of the muta- made in basing a diagnosis on GBM ap- rather than to make a positive molecular tions that contribute to autosomal pearance, especially in boys and females. diagnosis of TBMN.

372 Journal of the American Society of Nephrology J Am Soc Nephrol 24: 364–375, 2013 www.jasn.org SPECIAL ARTICLE

Table 6. Diagnosis of TBMN Characteristic Feature Sensitivity Specificity Comments Persistent glomerular hematuria, High (80%) Moderate TBMN is the most common cause; occurs in IgA disease minimal proteinuria, normal BP, too but often with higher urinary red blood cell counts and normal renal function and (less commonly) proteinuria Family history of hematuria Moderate (70%) High Family history of hematuria is also common in X-linked Alport syndrome Generally thinned GBM without 95% High focal lamellation Collagen IV a3a4a5 network 100% Moderate Supports but does not prove the diagnosis of TBMN present in GBM a5(IV) collagen chain present in skin Supports but does not prove the diagnosis of TBMN Hematuria segregates with 40% High COL4A3/COL4A4 Hematuria does not segregate with High High Linkage studies require careful characterization of other the COL4A5 locus family members but are possible with very few members Single mutation in COL4A3 or COL4A4 80% Very high

Recommendation 15 Genetic Counseling genetic testing and renal biopsy have Genetic testing for COL4A3 and TBMN is inherited, but the penetrance of excluded X-linked Alport syndrome COL4A4 mutations is not usually re- hematuria is only 70%.3 The de novo and coincidental renal disease. A renal quired for the diagnosis of TBMN. mutation rate is low, and almost all af- biopsy is mandatory prior to donation Screening for COL4A5 mutations to fected individuals have another family to assess renal damage. If an individual exclude X-linked Alport syndrome is member with the causative mutation, with TBMN proceeds with renal dona- often more important. but not necessarily hematuria.3 On aver- tion, he or she must be aware of the age, half the children of an individual risks and use nephroprotective strate- Monitoring and Treatment with TBMN inherit the causative muta- gies to minimize the effects of hyper- The prognosis of TBMN is usually good.3 tion but, because hematuria is incom- tension and proteinuria from the time However, some individuals develop pletely penetrant, fewer have hematuria. of surgery. hypertension, proteinuria, or renal im- The offspring of two parents with pairment, which are all risk factors for TBMN have a 25% risk of autosomal re- Pregnancy progression to end-stage renal failure. cessive Alport syndrome if both parents Risks are not usually increased during Again, there is preliminary support have a mutation in the same COL4A3 or pregnancy in women with TBMN if hy- from a single retrospective study in COL4A4 gene. pertension, proteinuria, and renal im- humans, a murine model of TBMN, pairment are not present. Preeclampsia is and experience in other forms of diabetic Recommendation 17 not more common. and nondiabetic renal disease that renin- All individuals with TBMN and their angiotensin blockade delays progression families should be advised of the diag- to end-stage renal failure in at-risk indi- nosisofTBMN,itsinheritednature, CONCLUSIONS viduals.52,66–68 and their low risk of renal failure. There are still unresolved issues in the Recommendation 16 Renal Transplantation diagnosis and management of patients Individuals with TBMN should be There have been many reports of success- with Alport syndrome and TBMN. Ran- assessed at presentation for poor prog- ful cadaveric renal transplants from do- domized controlled trials are expensive, nostic indicators (hypertension, pro- nors with TBMN.3,62,69 The risk for live and the results may take years. In the teinuria, renal impairment). Those donors with TBMN is less certain be- future, we are likely to rely more on with these features should be managed cause normal donors already have an registries, in which patients undergo by a nephrologist, and treatment increased risk of hypertension and mi- semi-standardized treatment and their should include an ACE inhibitor to de- croalbuminuria. clinical progress isupdated online, some- lay the onset of renal failure. Other in- times by the patients themselves. In dividuals with TBMN may be reviewed Recommendation 18 addition, the mutation database initia- every 1–2 years for hypertension, pro- Individuals with TBMN may be kidney tives will help explain how mutations in teinuria, and renal impairment by donors if they have normal BP, pro- autosomal recessive Alport syndrome their primary care provider. teinuria, and renal function, and if and TBMN affect clinical features. In

J Am Soc Nephrol 24: 364–375, 2013 Alport Syndrome and TBMN 373 SPECIAL ARTICLE www.jasn.org the future, whole genome sequencing is 9. Yoshioka K, Hino S, Takemura T, Maki S, 20. Rumpelt HJ, Langer KH, Schärer K, Straub E, likely to be the diagnostic test of choice Wieslander J, Takekoshi Y, Makino H, Thoenes W: Split and extremely thin glo- Kagawa M, Sado Y, Kashtan CE: Type IV merular basement membranes in hereditary because it examines all three Alport genes collagen alpha 5 chain. Normal distribution nephropathy (Alport’ssyndrome).Virchows simultaneously. In the meantime, diag- and abnormalities in X-linked Alport syn- Arch A Pathol Anat Histol 364: 225–233, nostic laboratories must improve their drome revealed by monoclonal antibody. 1974 methods to ensure detection of both Am J Pathol 144: 986–996, 1994 21. Gubler MC, Knebelmann B, Beziau A, Broyer mutations in autosomal recessive disease. 10. Barker DF, Hostikka SL, Zhou J, Chow LT, M, Pirson Y, Haddoum F, Kleppel MM, Oliphant AR, Gerken SC, Gregory MC, Antignac C: Autosomal recessive Alport Otherwise, TBMN or autosomal dom- Skolnick MH, Atkin CL, Tryggvason K: Iden- syndrome: Immunohistochemical study of inantAlportsyndromeisdiagnosed, tification of mutations in the COL4A5 colla- type IV collagen chain distribution. Kidney conditions in which the clinical impli- gengeneinAlportsyndrome.Science 248: Int 47: 1142–1147, 1995 cations are very different. 1224–1227, 1990 22. van der Loop FT, Monnens LA, Schröder CH, 11. Mochizuki T, Lemmink HH, Mariyama M, Lemmink HH, Breuning MH, Timmer ED, Antignac C, Gubler MC, Pirson Y, Verellen- Smeets HJ: Identification of COL4A5 defects Dumoulin C, Chan B, Schröder CH, Smeets in Alport’s syndrome by immunohistochem- ACKNOWLEDGMENTS HJ, et al: Identification of mutations in the istry of skin. Kidney Int 55: 1217–1224, 1999 alpha 3(IV) and alpha 4(IV) collagen genes in 23. Copelovitch L, Kaplan BS: Is genetic testing We would like to thank our patients with autosomal recessive Alport syndrome. Nat of healthy pre-symptomatic children with Alport syndrome and Thin Basement Mem- Genet 8: 77–81, 1994 possible Alport syndrome ethical? Pediatr 12. Feingold J, Bois E, Chompret A, Broyer M, Nephrol 21: 455–456, 2006 brane Nephropathy and their families. Gubler MC, Grünfeld JP: Genetic heteroge- 24. Hanson H, Storey H, Pagan J, Flinter F: The C.K. has received honoraria from Athena neity of Alport syndrome. Kidney Int 27: 672– value of clinical criteria in identifying patients Diagnostics, and the Alport Syndrome Treat- 677, 1985 with X-linked Alport syndrome. Clin J Am Soc ments and Outcomes Registry is engaged in 13. van der Loop FT, Heidet L, Timmer ED, van den Nephrol 6: 198–203, 2011 collaborative research with the Novartis In- Bosch BJ, Leinonen A, Antignac C, Jefferson 25. King K, Flinter FA, Nihalani V, Green PM: JA, Maxwell AP, Monnens LA, Schröder CH, Unusual deep intronic mutations in the stitute for Biomedical Research. Smeets HJ: Autosomal dominant Alport syn- COL4A5 gene cause X linked Alport syn- drome caused by a COL4A3 splicesitemuta- drome. Hum Genet 111: 548–554, 2002 tion. Kidney Int 58: 1870–1875, 2000 26. Hertz JM, Juncker I, Marcussen N: MLPA and DISCLOSURES 14. Cosio FG, Falkenhain ME, Sedmak DD: As- cDNA analysis improves COL4A5 mutation J.S., M.G., O.G., J.D., and F.F. have no conflicts of sociation of thin glomerular basement mem- detection in X-linked Alport syndrome. Clin brane with other glomerulopathies. Kidney Genet 74: 522–530, 2008 interest to declare. Int 46: 471–474, 1994 27.WangF,WangY,DingJ,YangJ:Detection 15. Jais JP, Knebelmann B, Giatras I, De Marchi of mutations in the COL4A5 gene by ana- M, Rizzoni G, Renieri A, Weber M, Gross O, lyzing cDNA of skin fibroblasts. Kidney Int 67: REFERENCES Netzer KO, Flinter F, Pirson Y, Verellen C, 1268–1274, 2005 Wieslander J, Persson U, Tryggvason K, 28. Tazon-Vega, B, Ars, E, Burset, M, Santin, S, 1. Hogg RJ, Harris S, Lawrence DM, Henning Martin P, Hertz JM, Schröder C, Sanak M, Ruiz, P, Fernandez-Llama, P, Ballarin, J & Torra, PH, Wigg N, Jureidini KF: Renal tract abnor- Krejcova S, Carvalho MF, Saus J, Antignac C, R: Genetic testing for X-linked Alport syn- malities detected in Australian preschool Smeets H, Gubler MC: X-linked Alport syn- drome by direct sequencing of COL4A5 children. J Paediatr Child Health 34: 420– drome: Natural history in 195 families and cDNA from hair root RNA samples. Am J 424, 1998 genotype- phenotype correlations in males. Kidney Dis 50: 257 e1-14, 2007 2. Ritchie CD, Bevan EA, Collier SJ: Importance JAmSocNephrol11: 649–657, 2000 29. Gross O, Netzer KO, Lambrecht R, Seibold of occult haematuria found at screening. Br 16. Hertz JM, Thomassen M, Storey H, Flinter F: S, Weber M: Meta-analysis of genotype- Med J 292: 681–683, 1986 Clinical utility gene card for Alport syndrome phenotype correlation in X-linked Alport syn- 3. Savige J, Rana K, Tonna S, Buzza M, Dagher Eur J Hum Genet 20: 6, 2012 drome: Impact on clinical counselling. Nephrol H, Wang YY: Thin basement membrane ne- 17. Gubler MC: Diagnosis of Alport syndrome Dial Transplant 17: 1218–1227, 2002 phropathy. Kidney Int 64: 1169–1178, 2003 without biopsy? Pediatr Nephrol 22: 621– 30. Kashtan CE: Alport syndrome and the X 4. Hudson BG, Tryggvason K, Sundaramoorthy 625, 2007 chromosome: Implications of a diagnosis of M, Neilson EG: Alport’s syndrome, Good- 18. Jais JP, Knebelmann B, Giatras I, De Marchi Alport syndrome in females. Nephrol Dial pasture’s syndrome, and type IV collagen. N M, Rizzoni G, Renieri A, Weber M, Gross O, Transplant 22: 1499–1505, 2007 Engl J Med 348: 2543–2556, 2003 Netzer KO, Flinter F, Pirson Y, Dahan K, 31. Kashtan CE: Renal transplantation in patients 5. Hasstedt SJ, Atkin CL: X-linked inheritance of Wieslander J, Persson U, Tryggvason K, with Alport syndrome. Pediatr Transplant 10: Alport syndrome: Family P revisited. Am J Martin P, Hertz JM, Schröder C, Sanak M, 651–657, 2006 Hum Genet 35: 1241–1251, 1983 Carvalho MF, Saus J, Antignac C, Smeets H, 32. Savige J, Colville D: Opinion: Ocular features 6. Persson U, Hertz JM, Wieslander J, Gubler MC: X-linked Alport syndrome: nat- aid the diagnosis of Alport syndrome. Nat Segelmark M: Alport syndrome in southern ural history and genotype-phenotype corre- Rev Nephrol 5: 356–360, 2009 Sweden. Clin Nephrol 64: 85–90, 2005 lations in girls and women belonging to 195 33. Proesmans W, Van Dyck M: Enalapril in chil- 7. Savige J, Ratnaike S, Colville D: Retinal abnor- families: A “European Community Alport dren with Alport syndrome. Pediatr Nephrol malities characteristic of inherited renal disease. Syndrome Concerted Action” study. JAm 19: 271–275, 2004 JAmSocNephrol22: 1403–1415, 2011 Soc Nephrol 14: 2603–2610, 2003 34. Kaito H, Nozu K, Iijima K, Nakanishi K, 8. Gubler M, Levy M, Broyer M, Naizot C, 19. Tan R, Colville D, Wang YY, Rigby L, Savige J: Yoshiya K, Kanda K, Przybyslaw Krol R, Gonzales G, Perrin D, Habib R: Alport’s syn- Alport retinopathy results from “severe” Yoshikawa N, Matsuo M: The effect of aldo- drome. A report of 58 cases and a review of COL4A5 mutations and predicts early renal sterone blockade in patients with Alport syn- the literature. Am J Med 70: 493–505, 1981 failure. Clin J Am Soc Nephrol 5: 34–38, 2010 drome. Pediatr Nephrol 21: 1824–1829, 2006

374 Journal of the American Society of Nephrology J Am Soc Nephrol 24: 364–375, 2013 www.jasn.org SPECIAL ARTICLE

35. Gross O, Licht C, Anders HJ, Hoppe B, Beck American Pediatric Renal Transplant Cooper- R: Assessment of long-term risks for living re- B, Tonshoff B, Hocker B, Wygoda S, Ehrich ative Study. Pediatr Nephrol 9: 679–684, 1995 lated kidney donors by 24-h blood pressure JH, Pape L, Konrad M, Rascher W, Dotsch J, 45. Temme J, Kramer A, Jager KJ, Lange K, monitoring and testing for microalbuminuria. Muller-Wiefel DE, Hoyer P, Knebelmann B, Peters F, Muller GA, Kramar R, Heaf JG, Clin Transplant 11: 415–419, 1997 Pirson Y, Grunfeld JP, Niaudet P, Cochat P, Finne P, Palsson R, Reisæter AV, Hoitsma AJ, 58. Kashtan CE: Women with Alport syndrome: Heidet L, Lebbah S, Torra R, Friede T, Lange Metcalfe W, Postorino M, Zurriaga O, Santos risks and rewards of kidney donation. Nephrol K, Muller GA, Weber M: Early angiotensin- JP, Ravani P, Jarraya F, Verrina E, Dekker FW, Dial Transplant 24: 1369–1370, 2009 converting enzyme inhibition in Alport syn- Gross O: Outcomes of male patients with Alport 59. Steele DJ, Michaels PJ: Case records of the drome delays renal failure and improves life syndrome undergoing renal replacement ther- Massachusetts General Hospital. Weekly clin- expectancy. Kidney Int 81:494–501, 2012 apy. Clin J Am Soc Nephrol 7: 1969–1976, 2012 icopathological exercises. Case 40-2004 - a 36. Gross O, Friede T, Hilgers R, Görlitz A, 46. Fleming SJ, Savage CO, McWilliam LJ, 42-year-old woman with long-standing he- Gavénis K, Ahmed R, Dürr U: Safety and ef- Pickering SJ, Ralston AJ, Johnson RW, Ackrill maturia. NEnglJMed351: 2851–2859, 2004 ficacy of the ACE-inhibitor ramipril in Alport P: Anti-glomerular basement membrane 60. Matsubara S, Ueda Y, Takahashi H, Nagai T, syndrome: The double-blind, randomized, antibody-mediated nephritis complicating Kuwata T, Muto S, Yamaguchi T, Takizawa T, placebo-controlled, multicenter phase III transplantation in a patient with Alport’ssyn- Suzuki M: Pregnancy complicated with Al- EARLY PRO-TECT Alport trial in pediatric drome. Transplantation 46: 857–859, 1988 port syndrome: a good obstetric outcome patients [published online July 1, 2012]. ISRN 47. Berardinelli L, Pozzoli E, Raiteri M, Canal R, and failure to diagnose an infant born to a Pediatr doi:10.5402/2012/436046 Tonello G, Tarantino A, Vegeto A: Renal mother with Alport syndrome by umbilical 37. Kashtan CE, Ding J, Gregory M, Gross O, transplantation in Alport’s syndrome. Per- cord immunofluorescence staining. JObstet Heidet L, Knebelmann B, Rheault M, Licht C: sonal experience in twelve patients. Contrib Gynaecol Res 35: 1109–1114, 2009 Clinical practice recommendations for the Nephrol 80: 131–134, 1990 61. Hood JC, Savige J, Hendtlass A, Kleppel MM, treatment of Alport syndrome: A statement 48. Lemmink HH, Schröder CH, Monnens LA, Huxtable CR, Robinson WF: Bull terrier hered- of the Alport Syndrome Research Collabo- Smeets HJ: The clinical spectrum of type IV itary nephritis: a model for autosomal dominant rative. Pediatr Nephrol 28:5–11, 2013 collagen mutations. Hum Mutat 9: 477–499, 1997 Alport syndrome. Kidney Int 47: 758–765, 1995 38. Koepke ML, Weber M, Schulze-Lohoff E, 49. Browne G, Brown PA, Tomson CR, Fleming S, 62. Ierino FL, Kanellis J: Thin basement mem- Beirowski B, Segerer S, Gross O: Nephro- Allen A, Herriot R, Pusey CD, Rees AJ, Turner brane nephropathy and renal transplantation. protective effect of the HMG-CoA-reductase AN: Retransplantation in Alport post-transplant Semin Nephrol 25: 184–187, 2005 inhibitor cerivastatin in a mouse model of anti-GBM disease. Kidney Int 65: 675–681, 63. Haas M: Alport syndrome and thin glomeru- progressive renal fibrosis in Alport syndrome. 2004 lar basement membrane nephropathy: A Nephrol Dial Transplant 22: 1062–1069, 50. Dagher H, Buzza M, Colville D, Jones C, practical approach to diagnosis. Arch Pathol 2007 Powell H, Fassett R, Wilson D, Agar J, Savige J: Lab Med 133: 224–232, 2009 39. Zeisberg M, Khurana M, Rao VH, Cosgrove A comparison of the clinical, histopathologic, 64. Pettersson E, Törnroth T, Wieslander J: Ab- D, Rougier JP, Werner MC, Shield CF, Werb and ultrastructural phenotypes in carriers of normally thin glomerular basement mem- Z, Kalluri R: Stage-specific action of matrix X-linked and autosomal recessive Alport’ssyn- brane and the Goodpasture epitope. Clin metalloproteinases influences progressive drome. Am J Kidney Dis 38: 1217–1228, 2001 Nephrol 33: 105–109, 1990 hereditary kidney disease. PLoS Med 3: 51. Rumpelt HJ: Hereditary nephropathy (Alport 65. Jefferson JA, Lemmink HH, Hughes AE, Hill e100, 2006 syndrome): Correlation of clinical data with CM, Smeets HJ, Doherty CC, Maxwell AP: 40. Ninichuk V, Gross O, Reichel C, Khandoga A, glomerular basement membrane alterations. Autosomal dominant Alport syndrome linked Pawar RD, Ciubar R, Segerer S, Belemezova Clin Nephrol 13: 203–207, 1980 to the type IV collage alpha 3 and alpha 4 E, Radomska E, Luckow B, Perez de Lema G, 52. Temme J, Peters F, Lange K, Pirson Y, Heidet genes (COL4A3 and COL4A4). Nephrol Dial Murphy PM, Gao JL, Henger A, Kretzler M, L, Torra R, Grunfeld JP, Weber M, Licht C, Transplant 12: 1595–1599, 1997 Horuk R, Weber M, Krombach F, Schlöndorff Müller GA, Gross O: Incidence of renal failure 66. The GISEN Group (Gruppo Italiano di Studi D, Anders HJ: Delayed chemokine receptor and nephroprotection by RAAS inhibition in Epidemiologici in Nefrologia): Randomised 1 blockade prolongs survival in collagen heterozygous carriers of X-chromosomal and placebo-controlled trial of effect of ramipril on 4A3-deficient mice with Alport disease. JAm autosomal recessive Alport mutations. Kid- decline in glomerular filtration rate and risk of Soc Nephrol 16: 977–985, 2005 ney Int 81: 779–783, 2012 terminal renal failure in proteinuric, non-diabetic 41. Gross O, Koepke ML, Beirowski B, Schulze- 53. Grünfeld JP, Noël LH, Hafez S, Droz D: Renal nephropathy. Lancet 349: 1857–1863, 1997 Lohoff E, Segerer S, Weber M: Nephropro- prognosis in women with hereditary nephri- 67. Ruggenenti P, Perna A, Remuzzi G; Gruppo tection by antifibrotic and anti-inflammatory tis. Clin Nephrol 23: 267–271, 1985 Italiano di Studi Epidemiologici in Nefro- effects of the vasopeptidase inhibitor 54. Gross O, Weber M, Fries JW, Müller GA: logia: ACE inhibitors to prevent end-stage AVE7688. Kidney Int 68: 456–463, 2005 Living donor from renal disease: When to start and why possibly 42. Sugimoto H, Mundel TM, Sund M, Xie L, relatives with mild urinary abnormalities in never to stop: a post hoc analysis of the REIN Cosgrove D, Kalluri R: -marrow-derived Alport syndrome: Long-term risk, benefit and trial results. Ramipril Efficacy in Nephropa- stem cells repair basement membrane col- outcome. Nephrol Dial Transplant 24: 1626– thy. JAmSocNephrol12: 2832–2837, 2001 lagen defects and reverse genetic kidney 1630, 2009 68. Gross O, Beirowski B, Koepke ML, Kuck J, disease. Proc Natl Acad Sci U S A 103: 55. Nakanishi K, Iijima K, Kuroda N, Inoue Y, Reiner M, Addicks K, Smyth N, Schulze- 7321–7326, 2006 Sado Y, Nakamura H, Yoshikawa N: Com- Lohoff E, Weber M: Preemptive ramipril 43. Prodromidi EI, Poulsom R, Jeffery R, parison of alpha5(IV) collagen chain expres- therapy delays renal failure and reduces renal Roufosse CA, Pollard PJ, Pusey CD, Cook HT: sion in skin with disease severity in women fibrosis in COL4A3-knockout mice with Al- Bone marrow-derived cells contribute to with X-linked Alport syndrome. JAmSoc port syndrome. Kidney Int 63: 438–446, 2003 regeneration and amelioration of Nephrol 9: 1433–1440, 1998 69. Sakai K, Muramatsu M, Ogiwara H, renal disease in a mouse model of Alport 56. Meleg-Smith S, Magliato S, Cheles M, Garola Kawamura T, Arai K, Aikawa A, Ohara T, syndrome. Stem Cells 24: 2448–2455, 2006 RE, Kashtan CE: X-linked Alport syndrome in Mizuiri S, Joh K, Naito I, Hasegawa A: Living 44. Kashtan CE, McEnery PT, Tejani A, Stablein females. Hum Pathol 29: 404–408, 1998 related kidney transplantation in a patient DM: Renal allograft survival according to 57. Eberhard OK, Kliem V, Offner G, Oldhafer K, with autosomal-recessive Alport syndrome. primary diagnosis: a report of the North Fangmann J, Pichlmay R, Koch KM, Brunkhorst Clin Transplant 17[Suppl 10]: 4–8, 2003

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