SPECIAL ARTICLE www.jasn.org Expert Guidelines for the Management of Alport Syndrome 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, 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 proteinuria; 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 kidney failure; and consid- for the patient with persistent hematuria, 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 collagen IV composi- The following recommendations de- least a year occurs in at least 1% of the tion;9 and mutations 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, hearing loss, 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 mutation 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 nephronophthisis. 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