5ec3d57c91e659d54b65d2f79efbefd4 320776.pdf 7ec183454b509aee2ce08a90984eb3042e1ce5ec 320776.pdf 1b54568bc91e382daa7fb013657ebb76f787cdb86f63e48cebec55a587089db0 320776.pdf Title: Diagnosis, management and treatment of the Alport syndrome – 2024 guideline on behalf of ERKNet, ERA and ESPN Subject: DOI: 10.1093/ndt/gfae265 Nephrology Dialysis Transplantation, 40, 6, 2-12-2024. Abstract: Glomerular nephropathy resulting from the genetic defects in COL4A3/4/5 genes including the classical Alport syndrome is the second most common hereditary kidney disease characterized by persistent haematuria progressing to the need for kidney replacement therapy, frequently associated with sensorineural deafness, and occasionally with ocular anomalies.Diagnosis and management of COL4A3/4/5 glomerulopathy is a great challenge due to its phenotypic heterogeneity, multiple modes of inheritance, variable expressivity, and disease penetrance of individual variants as well as imperfect prognostic and progression factors and scarce and limited clinical trials, especially in children.As a joint initiative of the European Rare Kidney disease reference Network (ERKNet), European Renal Association (ERA Genes&Kidney), and European Society for Paediatric Nephrology (ESPN) Inherited renal disorders working group, a team of experts including adult and paediatric nephrologists, kidney geneticists, audiologists, ophthalmologists, and a kidney pathologist were selected to perform a systematic literature review on 21 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions. The experts formulated recommendations and formally graded them at a consensus meeting with input from patient representatives and a voting panel of nephrologists representing all regions of the world.Genetic diagnostics comprising joint analysis of COL4A3/4/5 genes is already the key diagnostic test during the initial evaluation of an individual presenting with persistent haematuria, proteinuria, kidney failure of unknown origin, focal segmental sclerosis of unknown origin, and possibly cystic kidney disease. Early renin-angiotensin system blockade is the standard of care therapy; sodium-glucose cotransporter-2 inhibitors may be added in adults with proteinuria and chronic kidney disease. Relatives with heterozygous COL4A3/4/5 variants should only be considered as the last possible resource for living kidney donation.This guideline provides guidance for the diagnosis and management of individuals with pathogenic variants in COL4A3/4/5 genes. Keywords: Alport syndrome, collagen IV, glomerular basement membrane, haematuria, COL4A3 Author: Torra Roser, Lipska-Zietkiewicz Beata, Acke Frederic, Antignac Corinne, Becker Jan Ulrich, Cornec-Le Gall Emilie, van Eerde Albertien M., Feltgen Nicolas, Ferrari Rossella, Gale Daniel P., Gear Susie, Gross Oliver, Haeberle Stefanie, Heidet Laurence, Lennon Rachel, Massella Laura, Pfau Kristina, Pizarro Maria del Prado Venegas, Topaloglu Rezan, Wlodkowski Tanja, Zealey Heidi, Creator: OUP Producer: Acrobat Distiller 10.0.0 (Windows); modified using iTextSharp.LGPLv2.Core 3.7.4.0 CreationDate: Tue May 13 12:19:59 2025 CEST ModDate: Tue Oct 28 10:24:02 2025 CET Custom Metadata: yes Metadata Stream: yes Tagged: yes UserProperties: no Suspects: no Form: none JavaScript: no Pages: 16 Encrypted: no Page size: 595.276 x 782.362 pts Page rot: 0 File size: 943408 bytes Optimized: no PDF version: 1.3 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- BACKLJ+CaeciliaLTStd-Light Type 1C Custom yes yes yes 40 0 BACEEO+CaeciliaLTStd-Roman Type 1C WinAnsi yes yes no 41 0 BACELN+MTSY Type 1C Custom yes yes yes 100 0 BABNFG+CaeciliaLTStd-Bold Type 1C Custom yes yes yes 43 0 BACEEN+dummy-space Type 1C WinAnsi yes yes no 44 0 BACLKE+CaeciliaLTStd-Heavy Type 1C WinAnsi yes yes no 45 0 BACEEM+CaeciliaLTStd-Italic Type 1C WinAnsi yes yes no 48 0 MURLOV+ArialMT TrueType WinAnsi yes yes no 1 0 BACLOE+CaeciliaLTStd-LightItalic Type 1C WinAnsi yes yes no 39 0 BACMFE+CaeciliaLTStd-BoldItalic Type 1C WinAnsi yes yes no 42 0 BACMFD+CaeciliaLTStd-HeavyItalic Type 1C WinAnsi yes yes no 46 0 BACMED+RMTMI Type 1C Custom yes yes yes 47 0 BADDBM+RMTMIB Type 1C Custom yes yes yes 136 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2025-10-29 04:39:30 CET RepresentationInformation: 320776.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2025-10-28 10:24:20 CET Size: 943408 Format: PDF Version: 1.3 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf Profile: Tagged PDF PDFMetadata: Objects: 2794 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: false CenterWindow: false DisplayDocTitle: true NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: OneColumn PageMode: UseOutlines Language: English Outlines: Item: Title: INTRODUCTION Destination: section*.2 Item: Title: MATERIALS AND METHODS Destination: section*.4 Item: Title: Q1: XLAS AND ARAS: WHAT ARE THE DIFFERENCES AMONG THEM AND WHAT IS THEIR PREVALENCE? Destination: section*.6 Item: Title: Q2: WHAT ARE THE PENETRANCE AND PREVALENCE OF HETEROZYGOUS COL4A3/COL4A4 SINGLE PATHOGENIC VARIANTS? Destination: section*.8 Item: Title: Q3: IS THE TERM ‘DIGENIC’ JUSTIFIED IN AS? Destination: section*.10 Item: Title: Q4: WHEN TO ORDER ALPORT GENE TESTING? WHAT IS THE LIST OF CLINICAL AND/OR HISTOLOGICAL FINDINGS THAT REQUIRE EXCLUDING ALPORT DIAGNOSIS IN DIFFERENTIAL DIAGNOSTICS AND WHAT SHOULD BE DONE IN MINORS? Destination: section*.12 Children: Item: Title: 0.1 Histological findings that prompt genetic testing of COL4A3/4/5 genes Destination: subsection..0.0.1 Item: Title: 0.2 Panels that should include COL4A3/4/5 gene analysis Destination: subsection..0.0.2 Item: Title: Q5: SHOULD GENETIC TESTING IN RELATIVES BE ENCOURAGED? SHOULD IT BE LIMITED TO (FAMILY) VARIANT TESTING OR RATHER COVER ALL THREE GENES? SHOULD PARTNERS BE TESTED WHEN WISHING TO CREATE A FAMILY? Destination: section*.14 Item: Title: Q6: SHOULD ALPORT GENE TESTING BE INCLUDED IN GENE PANELS DESIGNED FOR KIDNEY DISEASES? Destination: section*.16 Item: Title: Q7: SHOULD ALPORT GENE TESTING BE INCLUDED ON THE LIST OF SECONDARY FINDINGS/ACTIONABLE FINDINGS? Destination: section*.18 Item: Title: Q8: GIVEN THE RELATIVELY HIGH FREQUENCY OF INDIVIDUALS WITH HETEROZYGOUS COL4A3/4 VARIANTS IN THE GENERAL POPULATION AND THEIR POTENTIALLY DETERIORATING EFFECT ON THE PHENOTYPE, SHOULD PATIENTS WITH PATHOGENIC COL4A3/4 VARIANTS BE SCREENED FOR OTHER KIDNEY DISEASES IN THE CLINICAL PRACTICE? Destination: section*.20 Item: Title: Q9: WHAT IS THE SENSITIVITY OF CURRENT GENETIC TESTS FOR AS? WHAT ARE THE POTENTIAL DIAGNOSTIC TOOLS IF NEXT-GENERATION SEQUENCING (NGS)-BASED GENETIC TESTING IS NEGATIVE? Destination: section*.22 Item: Title: Q10: WHAT IS THE ESTIMATED LIFELONG RELATIVE RISK OF STAGE 5 CKD IN INDIVIDUALS WITH HETEROZYGOUS COL4A3/COL4A4 VARIANTS VERSUS THAT IN THE GENERAL POPULATION? Destination: section*.24 Item: Title: Q11: WHAT IS THE ESTIMATED LIFELONG RELATIVE RISK AND AGE-RELATED RISK OF STAGE 5 CKD DEPENDING ON PATTERN OF INHERITANCE AND SEX? Destination: section*.26 Children: Item: Title: XLAS-Male Destination: section*.28 Item: Title: XLAS-Female Destination: section*.30 Item: Title: ARAS-both genders Destination: section*.32 Item: Title: Individuals with a heterozygous P/LP COL4A3/COL4A4 variant Destination: section*.34 Item: Title: Q12: WHAT IS THE SUGGESTED FOLLOW-UP FOR INDIVIDUALS WITH HETEROZYGOUS P/LP COL4A3/COL4A4 VARIANTS? Destination: section*.36 Item: Title: Q13: TO WHOM, WHEN, AND HOW SHOULD HEARING BE ASSESSED? Destination: section*.38 Item: Title: Q14: TO WHOM, WHEN AND HOW SHOULD OPHTHALMOLOGIC EXAM BE PERFORMED? Destination: section*.40 Item: Title: Q15: WHAT ARE THE PROGRESSION FACTORS IN AS? Destination: section*.42 Item: Title: Q16: WHAT IS THE ROLE OF KIDNEY BIOPSY IN PATIENTS WHO ALREADY HAVE A GENETIC DIAGNOSIS OF (OR FAMILY HISTORY OF CONFIRMED) AS? Destination: section*.44 Item: Title: Q17: WHEN (CONSIDERING BOTH AGE AND CLINICAL SITUATION) SHOULD RAS BLOCKERS BE STARTED IN A PATIENT WITH A COL4A3/4/5 VARIANT? Destination: section*.46 Children: Item: Title: Efficacy and dosing of RAS blockade Destination: section*.48 Item: Title: Safety of RAS-blockade and off-label use in children Destination: section*.50 Item: Title: Research objective RAS blockade in AS Destination: section*.52 Item: Title: Q18: SHOULD SGLT2-INHIBITORS BE USED IN AS? IF SO, WHEN SHOULD THEY BE PRESCRIBED? Destination: section*.54 Children: Item: Title: Efficacy of SGLT2i in AS Destination: section*.56 Item: Title: Safety of SGLT2i and off-label use in children Destination: section*.58 Item: Title: Research objective SGLT2i in AS Destination: section*.60 Item: Title: Q19: SHOULD FURTHER STUDIES BE PERFORMED IN A PATIENT PRESENTING AT DIAGNOSIS WITH NEPHROTIC SYNDROME IN WHOM A COL4A3/4/5 PATHOGENIC VARIANT IS IDENTIFIED? Destination: section*.62 Item: Title: Q20: COULD INDIVIDUALS WITH HETEROZYGOUS COL4A3/COL4A4/COL4A5 PATHOGENIC VARIANTS BE CONSIDERED AS LIVING DONORS? Destination: section*.64 Item: Title: Q21: WHAT IS THE PREVALENCE AND THE MANAGEMENT OF ALPORT POST-TRANSPLANT NEPHRITIS OR DE NOVO GBM DISEASE? Destination: section*.66 Item: Title: PATIENT NEEDS FOR PEOPLE WITH AS Destination: section*.68 Children: Item: Title: 0.3 What patients need at the point of their diagnosis Destination: subsection..0.0.3 Item: Title: 0.4 What patients need with ongoing management of their condition Destination: subsection..0.0.4 Item: Title: CLOSING REMARKS AND FUTURE PERSPECTIVES Destination: section*.70 Item: Title: SUPPLEMENTARY DATA Destination: section*.72 Item: Title: ACKNOWLEDGEMENTS Destination: section*.74 Item: Title: FUNDING Destination: section*.76 Item: Title: AUTHORS’ CONTRIBUTIONS Destination: section*.78 Item: Title: DATA AVAILABILITY STATEMENT Destination: section*.80 Item: Title: CONFLICT OF INTEREST STATEMENT Destination: section*.82 Item: Title: REFERENCES Destination: section*.84 Info: Title: Diagnosis, management and treatment of the Alport syndrome – 2024 guideline on behalf of ERKNet, ERA and ESPN Author: Torra Roser, Lipska-Zietkiewicz Beata, Acke Frederic, Antignac Corinne, Becker Jan Ulrich, Cornec-Le Gall Emilie, van Eerde Albertien M., Feltgen Nicolas, Ferrari Rossella, Gale Daniel P., Gear Susie, Gross Oliver, Haeberle Stefanie, Heidet Laurence, Lennon Rachel, Massella Laura, Pfau Kristina, Pizarro Maria del Prado Venegas, Topaloglu Rezan, Wlodkowski Tanja, Zealey Heidi, Subject: DOI: 10.1093/ndt/gfae265 Nephrology Dialysis Transplantation, 40, 6, 2-12-2024. Abstract: Glomerular nephropathy resulting from the genetic defects in COL4A3/4/5 genes including the classical Alport syndrome is the second most common hereditary kidney disease characterized by persistent haematuria progressing to the need for kidney replacement therapy, frequently associated with sensorineural deafness, and occasionally with ocular anomalies.Diagnosis and management of COL4A3/4/5 glomerulopathy is a great challenge due to its phenotypic heterogeneity, multiple modes of inheritance, variable expressivity, and disease penetrance of individual variants as well as imperfect prognostic and progression factors and scarce and limited clinical trials, especially in children.As a joint initiative of the European Rare Kidney disease reference Network (ERKNet), European Renal Association (ERA Genes&Kidney), and European Society for Paediatric Nephrology (ESPN) Inherited renal disorders working group, a team of experts including adult and paediatric nephrologists, kidney geneticists, audiologists, ophthalmologists, and a kidney pathologist were selected to perform a systematic literature review on 21 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions. The experts formulated recommendations and formally graded them at a consensus meeting with input from patient representatives and a voting panel of nephrologists representing all regions of the world.Genetic diagnostics comprising joint analysis of COL4A3/4/5 genes is already the key diagnostic test during the initial evaluation of an individual presenting with persistent haematuria, proteinuria, kidney failure of unknown origin, focal segmental sclerosis of unknown origin, and possibly cystic kidney disease. Early renin-angiotensin system blockade is the standard of care therapy; sodium-glucose cotransporter-2 inhibitors may be added in adults with proteinuria and chronic kidney disease. Relatives with heterozygous COL4A3/4/5 variants should only be considered as the last possible resource for living kidney donation.This guideline provides guidance for the diagnosis and management of individuals with pathogenic variants in COL4A3/4/5 genes. Keywords: Alport syndrome, collagen IV, glomerular basement membrane, haematuria, COL4A3 Creator: OUP Producer: Acrobat Distiller 10.0.0 (Windows); modified using iTextSharp.LGPLv2.Core 3.7.4.0 CreationDate: Tue May 13 12:49:59 CEST 2025 ModDate: Tue Oct 28 10:24:02 CET 2025 ID: 0xf092ae103a96be04a39630132bbe6046, 0x2fe71f28fa1660785a0930177e83212c Filters: FilterPipeline: FlateDecode FilterPipeline: DCTDecode Images: Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 227 ImageHeight: 148 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Fonts: Type1: Font: BaseFont: BACEEM+CaeciliaLTStd-Italic FontSubset: true FirstChar: 47 LastChar: 116 FontDescriptor: FontName: BACEEM+CaeciliaLTStd-Italic Flags: Serif, Nonsymbolic, Italic FontBBox: -166, -270, 1053, 915 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: BACELN+MTSY FontSubset: true FirstChar: 2 LastChar: 177 FontDescriptor: FontName: BACELN+MTSY Flags: Symbolic FontBBox: 0, -954, 1043, 796 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: BACLOE+CaeciliaLTStd-LightItalic FontSubset: true FirstChar: 38 LastChar: 121 FontDescriptor: FontName: BACLOE+CaeciliaLTStd-LightItalic Flags: Serif, Nonsymbolic, Italic FontBBox: -166, -267, 1033, 909 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: BACKLJ+CaeciliaLTStd-Light FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: BACKLJ+CaeciliaLTStd-Light Flags: Serif, Symbolic FontBBox: -164, -266, 1130, 908 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: BADDBM+RMTMIB FontSubset: true FirstChar: 62 LastChar: 62 FontDescriptor: FontName: BADDBM+RMTMIB Flags: Symbolic, Italic, ForceBold FontBBox: 0, -208, 994, 706 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: BACEEO+CaeciliaLTStd-Roman FontSubset: true FirstChar: 38 LastChar: 169 FontDescriptor: FontName: BACEEO+CaeciliaLTStd-Roman Flags: Serif, Nonsymbolic FontBBox: -167, -270, 1136, 926 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: BACMFE+CaeciliaLTStd-BoldItalic FontSubset: true FirstChar: 47 LastChar: 79 FontDescriptor: FontName: BACMFE+CaeciliaLTStd-BoldItalic Flags: Nonsymbolic, Italic, ForceBold FontBBox: -169, -273, 1082, 932 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: BABNFG+CaeciliaLTStd-Bold FontSubset: true FirstChar: 2 LastChar: 144 FontDescriptor: FontName: BABNFG+CaeciliaLTStd-Bold Flags: Serif, Symbolic, ForceBold FontBBox: -166, -273, 1141, 938 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: BACEEN+dummy-space FontSubset: true FirstChar: 32 LastChar: 32 FontDescriptor: FontName: BACEEN+dummy-space Flags: Nonsymbolic FontBBox: 0, 0, 0, 0 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: BACLKE+CaeciliaLTStd-Heavy FontSubset: true FirstChar: 40 LastChar: 146 FontDescriptor: FontName: BACLKE+CaeciliaLTStd-Heavy Flags: Nonsymbolic, ForceBold FontBBox: -170, -277, 1146, 970 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: BACMFD+CaeciliaLTStd-HeavyItalic FontSubset: true FirstChar: 47 LastChar: 86 FontDescriptor: FontName: BACMFD+CaeciliaLTStd-HeavyItalic Flags: Nonsymbolic, Italic, ForceBold FontBBox: -293, -277, 1108, 943 FontFile3: true Encoding: WinAnsiEncoding Font: BaseFont: BACMED+RMTMI FontSubset: true FirstChar: 60 LastChar: 62 FontDescriptor: FontName: BACMED+RMTMI Flags: Symbolic, Italic FontBBox: 0, -213, 987, 680 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true TrueType: Font: BaseFont: MURLOV+ArialMT FontSubset: true FirstChar: 32 LastChar: 121 FontDescriptor: FontName: MURLOV+ArialMT Flags: Nonsymbolic FontBBox: -664, -324, 2000, 1039 FontFile2: true Encoding: WinAnsiEncoding XMP: 2025-05-13T15:49:59+05:30 2025-10-28T09:24:02+00:00 2025-10-28T09:24:02+00:00 OUP Acrobat Distiller 10.0.0 (Windows); modified using iTextSharp.LGPLv2.Core 3.7.4.0 Alport syndrome, collagen IV, glomerular basement membrane, haematuria, COL4A3 VoR 10.1093/ndt/gfae265 1460-2385 Nephrology Dialysis Transplantation journal 40 10.1093/ndt/gfae265 https://doi.org/10.1093/ndt/gfae265 © The Author(s) 2024. Published by Oxford University Press on behalf of the ERA. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. All Rights Reserved application/pdf doi:10.1093/ndt/gfae265 © The Author(s) 2024. Published by Oxford University Press on behalf of the ERA. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Torra Roser Lipska-Zietkiewicz Beata Acke Frederic Antignac Corinne Becker Jan Ulrich Cornec-Le Gall Emilie van Eerde Albertien M. Feltgen Nicolas Ferrari Rossella Gale Daniel P. Gear Susie Gross Oliver Haeberle Stefanie Heidet Laurence Lennon Rachel Massella Laura Pfau Kristina Pizarro Maria del Prado Venegas Topaloglu Rezan Wlodkowski Tanja Zealey Heidi Oxford University Press DOI: 10.1093/ndt/gfae265 Nephrology Dialysis Transplantation, 40, 6, 2-12-2024. Abstract: Glomerular nephropathy resulting from the genetic defects in COL4A3/4/5 genes including the classical Alport syndrome is the second most common hereditary kidney disease characterized by persistent haematuria progressing to the need for kidney replacement therapy, frequently associated with sensorineural deafness, and occasionally with ocular anomalies.Diagnosis and management of COL4A3/4/5 glomerulopathy is a great challenge due to its phenotypic heterogeneity, multiple modes of inheritance, variable expressivity, and disease penetrance of individual variants as well as imperfect prognostic and progression factors and scarce and limited clinical trials, especially in children.As a joint initiative of the European Rare Kidney disease reference Network (ERKNet), European Renal Association (ERA Genes&Kidney), and European Society for Paediatric Nephrology (ESPN) Inherited renal disorders working group, a team of experts including adult and paediatric nephrologists, kidney geneticists, audiologists, ophthalmologists, and a kidney pathologist were selected to perform a systematic literature review on 21 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions. The experts formulated recommendations and formally graded them at a consensus meeting with input from patient representatives and a voting panel of nephrologists representing all regions of the world.Genetic diagnostics comprising joint analysis of COL4A3/4/5 genes is already the key diagnostic test during the initial evaluation of an individual presenting with persistent haematuria, proteinuria, kidney failure of unknown origin, focal segmental sclerosis of unknown origin, and possibly cystic kidney disease. Early renin-angiotensin system blockade is the standard of care therapy; sodium-glucose cotransporter-2 inhibitors may be added in adults with proteinuria and chronic kidney disease. Relatives with heterozygous COL4A3/4/5 variants should only be considered as the last possible resource for living kidney donation.This guideline provides guidance for the diagnosis and management of individuals with pathogenic variants in COL4A3/4/5 genes. 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