Alport syndrome: a unified classification of genetic disorders of collagen IV α345: a position paper of the Alport Syndrome Classification Working Group
2018; Elsevier BV; Volume: 93; Issue: 5 Linguagem: Inglês
10.1016/j.kint.2017.12.018
ISSN1523-1755
AutoresClifford E. Kashtan, Jie Ding, Guido Garosi, Laurence Heidet, Laura Massella, Koichi Nakanishi, Kandai Nozu, Alessandra Renieri, Michelle N. Rheault, Fang Wang, Oliver Groß,
Tópico(s)Coagulation, Bradykinin, Polyphosphates, and Angioedema
ResumoMutations in the genes COL4A3, COL4A4, and COL4A5 affect the synthesis, assembly, deposition, or function of the collagen IV α345 molecule, the major collagenous constituent of the mature mammalian glomerular basement membrane. These mutations are associated with a spectrum of nephropathy, from microscopic hematuria to progressive renal disease leading to ESRD, and with extrarenal manifestations such as sensorineural deafness and ocular anomalies. The existing nomenclature for these conditions is confusing and can delay institution of appropriate nephroprotective therapy. Herein we propose a new classification of genetic disorders of the collagen IV α345 molecule with the goal of improving renal outcomes through regular monitoring and early treatment. Mutations in the genes COL4A3, COL4A4, and COL4A5 affect the synthesis, assembly, deposition, or function of the collagen IV α345 molecule, the major collagenous constituent of the mature mammalian glomerular basement membrane. These mutations are associated with a spectrum of nephropathy, from microscopic hematuria to progressive renal disease leading to ESRD, and with extrarenal manifestations such as sensorineural deafness and ocular anomalies. The existing nomenclature for these conditions is confusing and can delay institution of appropriate nephroprotective therapy. Herein we propose a new classification of genetic disorders of the collagen IV α345 molecule with the goal of improving renal outcomes through regular monitoring and early treatment. Inherited forms of glomerular hematuria include disorders of basement membrane collagen (Alport syndrome, thin basement membrane nephropathy/benign familial hematuria, hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome), complement (C3 glomerulopathy), and the podocyte cytoskeleton (Epstein, Fechtner, Sebastian, and May Hegglin syndromes). Two of these disorders—Alport syndrome and a milder disorder previously known as benign familial hematuria or thin basement membrane nephropathy—have a common molecular basis. These conditions arise as a result of mutations in genes COL4A3, COL4A4, and COL4A5 that affect the synthesis, assembly, deposition, or function (or a combination of these) of the collagen IV α345 molecule, the major collagenous constituent of the mature mammalian glomerular basement membrane (GBM). This shared molecular etiology is heterogeneously expressed at the histologic and clinical levels, producing a complex array of disease phenotypes and transmission patterns that defies categorization into 2 distinct disorders. The need for a new classification system that would promote easier and earlier diagnosis and proper lifelong surveillance and treatment of Alport syndrome was discussed at the 2015 International Workshop on Alport Syndrome.1Gross O. Kashtan C.E. Rheault M.N. et al.Advances and unmet needs in genetic, basic and clinical science in Alport syndrome: report from the 2015 International Workshop on Alport Syndrome.Nephrol Dial Transplant. 2017; 32: 916-924PubMed Google Scholar It has been proposed that Alport syndrome and benign familial hematuria/thin basement membrane nephropathy be classified as forms of collagen IV–related renal disease,2Longo I. Porcedda P. Mari F. et al.COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome.Kidney Int. 2002; 61: 1947-1956Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar but this approach has not been generally adopted. As the use of next generation and whole exome sequencing in the evaluation of familial hematuria,3Fallerini C. Dosa L. Tita R. et al.Unbiased next generation sequencing analysis confirms the existence of autosomal dominant Alport syndrome in a relevant fraction of cases.Clin Genet. 2014; 86: 252-257Crossref PubMed Scopus (97) Google Scholar, 4Moriniere V. Dahan K. Hilbert P. et al.Improved mutation screening in familial hematuric nephropathies through next generation sequencing.J Am Soc Nephrol. 2014; 25: 2740-2751Crossref PubMed Scopus (106) Google Scholar familial proteinuria, and focal segmental glomerulosclerosis5Gast C. Pengelly R.J. Lyon M. et al.Collagen (COL4) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis.Nephrol Dial Transplant. 2016; 31: 961-970Crossref PubMed Scopus (149) Google Scholar, 6Xie J. Wu X. Ren H. et al.COL4A3 mutations cause focal segmental glomerulosclerosis.J Mol Cell Biol. 2014; 6: 498-505Crossref PubMed Scopus (38) Google Scholar, 7Malone A.F. Phelan P.J. Hall G. et al.Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis.Kidney Int. 2014; 86: 1253-1259Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 8Voskarides K. Damianou L. Neocleous V. et al.COL4A3/COL4A4 mutations producing focal segmental glomerulosclerosis and renal failure in thin basement membrane nephropathy.J Am Soc Nephrol. 2007; 18: 3004-3016Crossref PubMed Scopus (160) Google Scholar becomes more frequent, increased numbers of patients with mutations in the COL4A3, COL4A4, and COL4A5 genes will be identified and standardization of disease classification will be needed to minimize diagnostic confusion. Herein we propose the classification of all disorders arising from abnormalities of the collagen IV α345 molecule as forms of Alport syndrome. We choose to modify existing terminology rather than attempt to create a novel nomenclature. In this revised nomenclature, Alport syndrome encompasses a phenotypic spectrum extending from nonprogressive, renal-limited disease to progressive, multisystem disease and a genetic spectrum that includes X-linked, autosomal, and digenic inheritance. The results of this classification scheme are as follow: (i) a simplified diagnostic terminology that aims to improve early diagnosis and treatment of Alport syndrome; (ii) clarification that thinning of GBMs is a lesion description rather than a diagnosis; (iii) incorporation of patients with hematuria, thin GBMs, and heterozygous mutations in COL4A3 or COL4A4 into autosomal Alport syndrome, eliminating thin basement membrane nephropathy as a diagnostic entity; and (iv) the recognition of X-chromosomal female subjects and microhematuric autosomal heterozygotes as patients with Alport syndrome in whom there is a significant and not negligible risk of progressive renal disease. In standardizing the nomenclature for these disorders, we hope to ensure early diagnosis, genetic counseling, and appropriate monitoring and management of patients with genetic abnormalities affecting the collagen IV α345 molecule. We stress that all disorders of the collagen IV α345 molecule present a risk for development of progressive renal disease that can be delayed or possibly prevented by timely therapy. Although recent studies have demonstrated that early initiation of therapy with angiotensin-converting enzyme inhibitors delays progression of Alport syndrome to end-stage renal disease (ESRD),9Gross O. Licht C. Anders H. et al.Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy.Kidney Int. 2012; 81: 494-501Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 10Temme J. Peters F. Lange K. et al.Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations.Kidney Int. 2012; 81: 779-783Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar leading to expert recommendations promoting renin-angiotensin-aldosterone system (RAAS) blockade in proteinuric Alport patients,11Kashtan C.E. Ding J. Gregory M. et al.Clinical practice recommendations for the treatment of Alport syndrome: a statement of the Alport Syndrome Research Collaborative.Pediatr Nephrol. 2013; 28: 5-11Crossref PubMed Scopus (99) Google Scholar, 12Savige J. Gregory M. Gross O. et al.Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy.J Am Soc Nephrol. 2013; 24: 364-375Crossref PubMed Scopus (253) Google Scholar management guidelines are inconsistently applied. For example, only 66% of participants in the ATHENA Natural History Study in Alport Syndrome Patients with declining renal function were receiving RAAS blockade.13Rheault M. Gross O. Appel G. et al.Change in glomerular filtration rate and renal biomarkers in patients with chronic kidney disease due to Alport syndrome: interim results from the Athena study, a prospectively designed natural history study.Nephrol Dial Transplant. 2016; 31: 1126Crossref Google Scholar A prospective study of RAAS blockade in Alport patients with heterozygous mutations found a mean time from appearance of the first symptom to diagnosis of 8.1 ± 14.2 years; at the time of starting RAAS blockade, 5.4% of patients had an estimated glomerular filtration rate <60 ml/min and 67.6% had proteinuria.14Stock J. Kuenanz J. Glonke N. et al.Prospective study on the potential of RAAS blockade to halt renal disease in Alport syndrome patients with heterozygous mutations.Pediatr Nephrol. 2017; 32: 131-137Crossref PubMed Scopus (24) Google Scholar These observations support the need to ameliorate the phenotypic complexity that may lead to late diagnosis and therapeutic intervention, resulting potentially in preventable ESRD in older patients. We expect that this new classification will improve the prognosis of patients presently diagnosed as benign familial hematuria or thin basement membrane nephropathy but not followed or treated or both due to the erroneous assumption of complete benignity. To us this benefit significantly outweighs the possible harm of classifying a patient with a benign prognosis as having a potentially progressive disorder. Collagen IV α345 molecules associate in networks that interact with laminin-521, agrin, nidogen, and other proteins to form mature GBMs.15Chen Y.M. Miner J.H. Glomerular basement membrane and related glomerular disease.Transl Res. 2012; 160: 291-297Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Collagen IV α345 molecules are heterotrimeric moieties created by the specific association of α3, α4, and α5 collagen IV chains in a 1:1:1 ratio. These chains are encoded by the genes COL4A3, COL4A4, and COL4A5, respectively. The COL4A3 and COL4A4 genes reside on chromosome 2 while the COL4A5 gene is located on the X chromosome. Disease-causing mutations in these genes may alter the synthesis, assembly, deposition, or function (or a combination of these) of α345(IV) molecules. The diseases caused by mutations in these genes are transmitted in an X-linked manner in the case of COL4A5 mutations, as autosomal disorders when the mutation or mutations are located in the COL4A3 or COL4A4 genes or as digenic inheritance when a combination of 2 mutations in different genes occurs.16Mencarelli M.A. Heidet L. Storey H. et al.Evidence of digenic inheritance in Alport syndrome.J Med Genet. 2015; 52: 163-174Crossref PubMed Scopus (100) Google Scholar Numerous studies of X-linked and autosomal Alport syndrome in mice, dogs, and humans have documented abnormalities of α345(IV) in basement membranes. COL4A5 mutations that interfere with the synthesis of the α5(IV) chain, such as deletions, frame shift mutations, and nonsense mutations, are associated with loss of expression of α345(IV) in basement membranes and a severe disease phenotype in hemizygous male subjects,17Jais J.P. Knebelmann B. Giatras I. et al.X-linked Alport syndrome: natural history in 195 families and genotype-phenotype correlations in males.J Am Soc Nephrol. 2000; 11: 649-657Crossref PubMed Google Scholar, 18Naito I. Kawai S. Nomura S. et al.Relationship between COL4A5 gene mutation and distribution of type IV collagen in male X-linked Alport syndrome.Kidney Int. 1996; 50: 304-311Abstract Full Text PDF PubMed Scopus (76) Google Scholar while the effects of splicing and missense mutations on α345(IV) expression and clinical phenotype are more variable.17Jais J.P. Knebelmann B. Giatras I. et al.X-linked Alport syndrome: natural history in 195 families and genotype-phenotype correlations in males.J Am Soc Nephrol. 2000; 11: 649-657Crossref PubMed Google Scholar In X-linked Alport syndrome, renal disease is frequently associated with progressive sensorineural deafness and specific ocular lesions such as perimacular flecks and lenticonus. Mutations in both alleles of COL4A3 or COL4A4 cause autosomal recessive Alport syndrome and include deletion, nonsense, frame shift, splicing, and missense alterations. Genotype-phenotype correlations for autosomal recessive Alport syndrome are less robust than those for X-linked Alport syndrome, but lack of expression of the α345(IV) network in basement membranes is associated with a severe phenotype.19Storey H. Savige J. Sivakumar V. et al.COL4A3/COL4A4 mutations and features in individuals with autosomal recessive Alport syndrome.J Am Soc Nephrol. 2013; 24: 1945-1954Crossref PubMed Scopus (92) Google Scholar, 20Oka M. Nozu K. Kaito H. et al.Natural history of genetically proven autosomal recessive Alport syndrome.Pediatr Nephrol. 2014; 29: 1535-1544Crossref PubMed Scopus (42) Google Scholar As in X-linked Alport syndrome, sensorineural deafness and ocular lesions frequently accompany renal disease in patients with autosomal recessive Alport syndrome. Autosomal recessive inheritance may be suggested by similar severity of disease in male and female siblings, parental consanguinity, or microscopic hematuria in the father or in both parents of a severely affected boy. Heterozygous mutations in COL4A3 and COL4A4 are associated with a spectrum of phenotypes ranging from complete absence of detectable symptomatology through isolated, asymptomatic hematuria to progressive renal disease, sensorineural deafness, and ocular abnormalities (autosomal dominant Alport syndrome).2Longo I. Porcedda P. Mari F. et al.COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome.Kidney Int. 2002; 61: 1947-1956Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar Within a family, the phenotype associated with a heterozygous mutation in COL4A3 or COL4A4 can vary significantly. The reasons for this variability of expression/incomplete penetrance are likely manifold, including modifier genes that ameliorate or exacerbate the effects of mutations on synthesis, assembly, or function (or a combination of these) of α345(IV)21Voskarides K. Stefanou C. Pieri M. et al.A functional variant in NEPH3 gene confers high risk of renal failure in primary hematuric glomerulopathies: evidence for predisposition to microalbuminuria in the general population.PLoS One. 2017; 12: e0174274Crossref PubMed Scopus (17) Google Scholar and factors such as smoking, high blood pressure, and dietary levels of salt and animal protein. The phenotype resulting from heterozygous mutations in COL4A3 and COL4A4 is transmitted in an autosomal dominant fashion. Genotype-phenotype correlations have yet to be established. Collagen IV α345 is nearly always detectable in basement membranes of animals and individuals with heterozygous COL4A3 and COL4A4 mutations.22Frasca G.M. Onetti Muda A. Mari F. et al.Thin glomerular basement membrane disease: clinical significance of a morphological diagnosis—a collaborative study of the Italian Renal Immunopathology Group.Nephrol Dial Transplant. 2005; 20: 545-551Crossref PubMed Scopus (24) Google Scholar Generally speaking, individuals with heterozygous COL4A3 and COL4A4 mutations who do exhibit progressive nephropathy reach ESRD significantly later in life than male subjects with X-linked Alport syndrome or individuals with autosomal recessive Alport syndrome.23Pescucci C. Mari F. Longo I. et al.Autosomal-dominant Alport syndrome: natural history of a disease due to COL4A3 or COL4A4 gene.Kidney Int. 2004; 65: 1598-1603Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 24Pochet J.M. Bobrie G. Landais P. et al.Renal prognosis in Alport's and related syndromes: influence of the mode of inheritance.Nephrol Dial Transplant. 1989; 4: 1016-1021PubMed Google Scholar Specific ocular lesions such as lenticonus and maculopathy that are common in people with X-linked or autosomal recessive Alport syndrome are unusual in people with heterozygous mutations in COL4A3 and COL4A4, but have been reported.25Colville D. Wang Y.Y. Jamieson R. et al.Absence of ocular manifestations in autosomal dominant Alport syndrome associated with haematological abnormalities.Ophthalmic Genet. 2000; 21: 217-225Crossref PubMed Google Scholar, 26Rosado C. Bueno E. Felipe C. et al.Study of the true clinical progression of autosomal dominant Alport syndrome in a European population.Kidney Blood Press Res. 2015; 40: 435-442Crossref PubMed Scopus (16) Google Scholar Sensorineural deafness is less common in people with heterozygous mutations in COL4A3 and COL4A4 than in people with X-linked or autosomal recessive Alport syndrome and tends to manifest later in life.26Rosado C. Bueno E. Felipe C. et al.Study of the true clinical progression of autosomal dominant Alport syndrome in a European population.Kidney Blood Press Res. 2015; 40: 435-442Crossref PubMed Scopus (16) Google Scholar Increased application of next generation and whole exome sequencing in the evaluation of familial renal disease has led to the identification of families transmitting heterozygous mutations in COL4A3 and COL4A4 in which the renal phenotype is mainly characterized by proteinuria, with minimal and in some cases absence of hematuria, and kidney biopsy shows focal segmental glomerulosclerosis.7Malone A.F. Phelan P.J. Hall G. et al.Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis.Kidney Int. 2014; 86: 1253-1259Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 27Feltran L.S. Varela P. Silva E.D. et al.Targeted next-generation sequencing in Brazilian children with nephrotic syndrome submitted to renal transplant.Transplantation. 2017; 101: 905-2912Crossref Scopus (12) Google Scholar, 28McCarthy H.J. Bierzynska A. Wherlock M. et al.Simultaneous sequencing of 24 genes associated with steroid-resistant nephrotic syndrome.Clin J Am Soc Nephrol. 2013; 8: 637-648Crossref PubMed Scopus (143) Google Scholar, 29Wu Y. Hu P. Xu H. et al.A novel heterozygous COL4A4 missense mutation in a Chinese family with focal segmental glomerulosclerosis.J Cell Mol Med. 2016; 20: 2328-2332Crossref PubMed Scopus (21) Google Scholar Based on our definition of Alport syndrome as a genetic disorder of the α345 collagen IV molecule, these patients and families have autosomal dominant Alport syndrome. At present the available data is insufficient to assess the importance of hematuria in determining renal outcomes in these patients. Recently coexisting mutations in COL4A3, COL4A4, or COL4A5 were reported to cause an Alport syndrome phenotype with digenic inheritance.16Mencarelli M.A. Heidet L. Storey H. et al.Evidence of digenic inheritance in Alport syndrome.J Med Genet. 2015; 52: 163-174Crossref PubMed Scopus (100) Google Scholar This is a new form of non-Mendelian inheritance that simulates in some cases autosomal recessive inheritance (digenic inheritance with mutation in trans and 25% recurrence risk) and in some others autosomal dominant inheritance (mutations in cis with 50% recurrence risk). However in the case of a combination of a COL4A5 mutation with a mutation in COL4A3 or COL4A4, the pattern of inheritance does not resemble any Mendelian process and family-specific risk assessment is needed.16Mencarelli M.A. Heidet L. Storey H. et al.Evidence of digenic inheritance in Alport syndrome.J Med Genet. 2015; 52: 163-174Crossref PubMed Scopus (100) Google Scholar Although the finding of thin GBMs in a patient with isolated hematuria has traditionally been associated with good renal outcomes, it has been clear for many years that patients with GBM thinning may exhibit progressive renal disease.30Tiebosch A.T. Frederik P.M. van Breda Vriesman P.J. et al.Thin-basement-membrane nephropathy in adults with persistent hematuria.N Engl J Med. 1989; 320: 14-18Crossref PubMed Scopus (165) Google Scholar GBM thinning is a pathologic finding that can be found in young male subjects with X-linked Alport syndrome, female subjects of any age with X-linked Alport syndrome, young male and female subjects with autosomal recessive Alport syndrome, and male and female subjects with heterozygous mutations in the COL4A3 and COL4A4 genes who may or may not exhibit progressive renal disease. Thus, GBM thinning does not constitute a distinct clinical entity or allow accurate prognostication in the absence of other clinical, pathologic, pedigree, and genetic data. In our view, “thin basement membrane nephropathy” is no longer a clinically useful term and should be discarded, because it tends to underestimate the risk of progressive kidney disease, potentially depriving an affected individual of therapy that can delay or possibly prevent ESRD. The new classification scheme categorizes genetic diseases of collagen IV α345 into 3 types of Alport syndrome: X-linked, autosomal, and digenic (Table 1).Table 1New classification system for Alport syndrome and related disordersInheritanceAffected gene(s)Genetic stateCommentsEstimated risk of ESRDX-linkedCOL4A5Hemizygous (male subjects)Rate of progression to ESRD and timing of extrarenal manifestations strongly influenced by genotype100%Heterozygous (female subjects)Risk factors for progression: gross hematuria, SNHL, proteinuria, GBM thickening and lamellationUp to 25%AutosomalCOL4A3 or COL4A4Recessive (homozygous or compound heterozygous)Rate of progression to ESRD and timing of extrarenal manifestations strongly influenced by genotype100%DominantHematuriaIncludes patients previously diagnosed as TBMN/BFHRisk factors for progression: proteinuria, FSGS, GBM thickening and lamellation, SNHL, or evidence of progression in patient or family, genetic modifiers20% or more among those with risk factors for progression, 200,000 people if that drug would only be relevant to an orphan subset that comprises <200,000 people. Consequently this new classification scheme should not impair orphan-drug designation for therapies aimed at slowing renal disease progression in Alport syndrome, as the relevant patient population would represent a subset of the disease. In advocating for this new classification scheme, we recognize that a diagnosis of Alport syndrome is currently an ominous one, implying progression to ESRD in patients and in their descendants. Under this new scheme, patients who previously would have been given a diagnosis (thin basement membrane nephropathy) typically associated with good outcomes would henceforth receive a diagnosis (Alport syndrome) associated with poor outcomes. Similarly, affected female subjects in families with X-linked Alport syndrome would be diagnosed with Alport syndrome, rather than being described as carriers of Alport syndrome. The emotional trauma associated with a diagnosis of Alport syndrome can be mitigated by providing patients and their families with individualized prognostic information based on clinical findings, family history, and results of genetic testing, as well as the positive findings of recent studies of therapeutic outcomes.9Gross O. Licht C. Anders H. et al.Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy.Kidney Int. 2012; 81: 494-501Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 10Temme J. Peters F. Lange K. et al.Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations.Kidney Int. 2012; 81: 779-783Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar The impact of an erroneous prediction of benign outcome should not be underestimated, as described by women with X-linked Alport syndrome (http://www.healthtalk.org/peoples-experiences/long-term-conditions/alport-syndrome/being-female-carrier-alport-syndrome). The success of this new scheme in clinical practice will require focused education of physicians and patients and acceptance of the notion that Alport syndrome is not always a progressive disorder. On the other hand, the new scheme—after its wide dissemination and education—has the potential to delay or prevent ESRD in numerous individuals with heterozygous mutations in COL4A3, COL4A4, or COL4A5. For the health of patients, the prevention of ESRD cases previously missed is surely to be preferred to the reassuring praxis of considering these heterozygous individuals as patients with a benign condition. Diagnosis and classification should lead to initiation of a plan for monitoring and treatment, according to current practice recommendations.11Kashtan C.E. Ding J. Gregory M. et al.Clinical practice recommendations for the treatment of Alport syndrome: a statement of the Alport Syndrome Research Collaborative.Pediatr Nephrol. 2013; 28: 5-11Crossref PubMed Scopus (99) Google Scholar, 12Savige J. Gregory M. Gross O. et al.Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy.J Am Soc Nephrol. 2013; 24: 364-375Crossref PubMed Scopus (253) Google Scholar The recommendations presented in Table 2 are intended to apply to any individual with a mutation in COL4A3, COL4A4, or COL4A5 who has hematuria, regardless of whether that mutation is hemizygous, heterozygous, biallelic, or digenic. COL4A3/COL4A4 heterozygotes with proteinuria are candidates for angiotensin blockade whether or not they have hematuria. As new therapies for Alport syndrome become available, with potentially greater risks than angiotensin-converting enzyme inhibition, early and accurate diagnosis and monitoring will become increasingly important.Table 2Clinical practice recommendations for monitoring and treatment of Alport syndromeHematuria with normal UACRaUrine albumin-creatinine ratio. and UPCRbUrine protein-creatinine ratio.Annual blood pressure, serum creatinine, UACR, UPCRReport outcome to national or international registryHematuria + microalbuminuriaIncrease monitoring to every 6 moConsider ACEi,cAngiotensin-converting enzyme inhibitor. especially for- patients with severe mutations (deletion, nonsense, frameshift, splicing)- SNHLdSensorineural hearing loss.- family history of ESRD before age 30 yrReport outcome to national or international registryHematuria + overt proteinuriaMonitor every 6 moStart ACEi, dose according to published recommendations11Kashtan C.E. Ding J. Gregory M. et al.Clinical practice recommendations for the treatment of Alport syndrome: a statement of the Alport Syndrome Research Collaborative.Pediatr Nephrol. 2013; 28: 5-11Crossref PubMed Scopus (99) Google Scholar, 12Savige J. Gregory M. Gross O. et al.Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy.J Am Soc Nephrol. 2013; 24: 364-375Crossref PubMed Scopus (253) Google Scholar;Effective contraception recommended for female subjects of child-bearing ageReport outcome to national or international registryProgressive proteinuria (despite ACEi)Consider add on therapy, such as- stringent blood pressure control including ARBs,eAngiotensin receptor blocker. aldosterone-antagonists, calcium channel blockers, diuretics- statins in patients with high cholesterol levels or nephrotic patients with dyslipoproteinemia- paricalcitol in patients with secondary hyperparathyroidismWatch for future upcoming therapiesReport outcome to national or international registryACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ESRD, end-stage renal disease; SNHL, sensorineural hearing loss; UACR, urine albumin-creatinine ratio; UPCR, urine protein-creatinine ratio.These recommendations apply for all types of Alport syndrome according to the new classification scheme.a Urine albumin-creatinine ratio.b Urine protein-creatinine ratio.c Angiotensin-converting enzyme inhibitor.d Sensorineural hearing loss.e Angiotensin receptor blocker. Open table in a new tab ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ESRD, end-stage renal disease; SNHL, sensorineural hearing loss; UACR, urine albumin-creatinine ratio; UPCR, urine protein-creatinine ratio. These recommendations apply for all types of Alport syndrome according to the new classification scheme. Patient registries and advocacy groups will have major roles to play in the dissemination of this classification scheme and assessment of its clinical impact. We urge clinicians to inform their patients with Alport syndrome about these registries and advocacy groups (Table 3).Table 3Alport syndrome registries and patient advocacy organizationsRegistriesAlport Syndrome Treatments and Outcomes Registrywww.alportregistry.orgEuropean Alport Registrywww.alport.deFrench Alport RegisryNational database on Rare Diseases (BNDMR; http://www.bndmr.fr) and the Rare Disease Cohorts (RADICO; http://www.radico.fr/fr/).Centre de Reference des Maladies Renales Hereditaires de l’Enfant et de l’Adulte (MARHEA; www.soc-nephrologie.org/marhea/).Chinese Alport Registryhttp://chrdb.edc-china.com.cn/login.jspItalian Alport Registry and Biobankhttp://www.biobank.unisi.it/Patient Advocacy OrganizationsAlport Syndrome Foundation (USA)www.alportsyndrome.orgAlportUKwww.alportuk.orgAlport Foundation of Australiawww.alport.org.auAIRG-Francewww.airg-france.frAlport Syndrome.ca (Canada)www.alportsyndrome.caAlport Support Group (Germany)www.alport-selbsthilfe.deAlport Syndrome Parent Association (China)site.henizaiyiqi.com/alportIsrael Alport Foundationwww.alport.co.il/Alport Syndrome Association (Italy)www.asalonlus.it Open table in a new tab All the authors declared no competing interests. The Alport Syndrome Treatments and Outcomes Registry (ASTOR) is supported by the Alport Syndrome Foundation, the Kenneth and Claudia Silverman Family Foundation, and the Schuman and Pedersen families. ASTOR participates in the ATHENA and Study of RG-012 in Male Subjects With Alport Syndrome (HERA) studies sponsored by Regulus Therapeutics and the Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients With Alport Syndrome (CARDINAL) study sponsored by Reata Pharmaceuticals and receives research support from Novartis Institute for Biomedical Research. The French Alport Registry is supported by the French Association for the Information and Research on Genetic Renal Diseases (AIRG-France), the National database on Rare Diseases (BNDMR; http://www.bndmr.fr), and the Rare Disease Cohorts (RADICO; http://www.radico.fr/fr/) and participates in the ATHENA study sponsored by Regulus Therapeutics. The Italian registry of Alport syndrome is supported by Italian Association of Alport Syndrome (ASAL; www.asalonlus.it) by donations in favor of Graziano and Marco Laurini and the correlated biobank is within the Telethon Network of Genetics Biobanks (TNGB; project no. GTB12001). The European Alport Registry was supported by the French Association for the Information and Research on Genetic Renal Diseases (AIRG-France) and is maintained as German Alport Registry, which participates in the ATHENA Study sponsored by Regulus Therapeutics.
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