Multizentrische Evaluation des unklaren chronischen Nierenversagens vor Nierentransplantation

• Antragsteller: Professor Dr. Jan Halbritter
• Fachliche Zuordnung: Nephrologie
• Förderung: Förderung von 2020 bis 2023
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 438567369

• Erstellungsjahr: 2024

Zusammenfassung der Projektergebnisse

The overall aim of the project was to establish a multicenter cohort of patients with undetermined ESRD awaiting kidney transplantation (KTx) in order to answer the following questions: i) prevalence of undetermined ESRD on KTx-waitlists ii) proportion of inherited kidney disease among patients with undetermined ESRD iii) discovery of novel genetic causes among patients with undetermined ESRD. Although hampered by a delay in patient recruitment, the mutlicenter cohort grew to about 500 patients and is still growing for a continued and consolidated enrollment phase. With this preliminary sample size, the project already yielded significant results, notably from the recruitment at two major sites (University Hospital Leipzig / Charité Berlin). The prevalence of undetermined ESRD according to unified criteria ranged at 40-50%. Upon genetic analysis, PKD1/2 and COL4A3/A4/A5 were by far the most frequent findings, followed by a multitude of more rare genetic kidney diseases (UMOD, HNF1B, PAX2 etc.). The diagnostic yield was 27-28% when including patients with ADPKD. Known genetic causes included numerous phenocopies and atypical clinical presentations, in part due to somatic mosaicism (PBX1), monoallelic gene expression (EYA1), and allelic effects (LMNA). Among genetically unresolved cases, the project led to identification and characterizaiton of three novel causes of inherited syndromic disorders with variable occurence of CKD (ROBO1, POU3F2, PHIP).

Projektbezogene Publikationen (Auswahl)

• Challenging Disease Ontology by Instances of Atypical PKHD1 and PKD1 Genetics. Frontiers in Genetics, 12.
  de Fallois, Jonathan; Schönauer, Ria; Münch, Johannes; Nagel, Mato; Popp, Bernt & Halbritter, Jan
  
• Posttransplant nephrotic syndrome resulting from NELL1-positive membranous nephropathy. American Journal of Transplantation, 21(9), 3175-3179.
  Münch, Johannes; Krüger, Bastian M.; Weimann, Antje; Wiech, Thorsten; Reinhard, Linda; Hoxha, Elion; Pfister, Frederick & Halbritter, Jan
  
• Biallelic pathogenic variants in roundabout guidance receptor 1 associate with syndromic congenital anomalies of the kidney and urinary tract. Kidney International, 101(5), 1039-1053.
  Münch, Johannes; Engesser, Marie; Schönauer, Ria; Hamm, J. Austin; Hartig, Christin; Hantmann, Elena; Akay, Gulsen; Pehlivan, Davut; Mitani, Tadahiro; Coban, Akdemir Zeynep; Tüysüz, Beyhan; Shirakawa, Toshihiko; Dateki, Sumito; Claus, Laura R.; van Eerde, Albertien M.; Smol, Thomas; Devisme, Louise; Franquet, Hélène; Attié-Bitach, Tania ... & Halbritter, Jan
  
• Defective claudin-10 causes a novel variation of HELIX syndrome through compromised tight junction strand assembly. Genes & Diseases, 9(5), 1301-1314.
  Sewerin, Sebastian; Piontek, Jörg; Schönauer, Ria; Grunewald, Sonja; Rauch, Angelika; Neuber, Steffen; Bergmann, Carsten; Günzel, Dorothee & Halbritter, Jan
  
• Genetics in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney International, 101(6), 1126-1141.
  Köttgen, Anna; Cornec-Le, Gall Emilie; Halbritter, Jan; Kiryluk, Krzysztof; Mallett, Andrew J.; Parekh, Rulan S.; Rasouly, Hila Milo; Sampson, Matthew G.; Tin, Adrienne; Antignac, Corinne; Ars, Elisabet; Bergmann, Carsten; Bleyer, Anthony J.; Bockenhauer, Detlef; Devuyst, Olivier; Florez, Jose C.; Fowler, Kevin J.; Franceschini, Nora; Fukagawa, Masafumi ... & Gharavi, Ali G.
  
• Modelling polycystic liver disease progression using age-adjusted liver volumes and targeted mutational analysis. JHEP Reports, 4(11), 100579.
  Sierks, Dana; Schönauer, Ria; Friedrich, Anja; Hantmann, Elena; de Fallois, Jonathan; Linder, Nikolas; Fischer, Janett; Herber, Adam; Bergmann, Carsten; Berg, Thomas & Halbritter, Jan
  
• Novel somatic PBX1 mosaicism likely masking syndromic CAKUT in an adult with bilateral kidney hypoplasia. Clinical Kidney Journal, 15(7), 1333-1339.
  Petzold, Friederike; Jin, Wenjun; Hantmann, Elena; Korbach, Katharina; Schönauer, Ria & Halbritter, Jan
  
• Systematic assessment of monogenic etiology in adult‐onset kidney stone formers undergoing urological intervention–evidence for genetic pretest probability. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 190(3), 279-288.
  Schönauer, Ria; Scherer, Lotte; Nemitz‐Kliemchen, Melanie; Hagemann, Tobias; Hantmann, Elena; Seidel, Anna; Müller, Luise; Kehr, Stephanie; Voigt, Cornelia; Stolzenburg, Jens‐Uwe & Halbritter, Jan
  
• The diagnostic value of native kidney biopsy in low grade, subnephrotic, and nephrotic range proteinuria: A retrospective cohort study. PLOS ONE, 17(9), e0273671.
  de Fallois, Jonathan; Schenk, Soeren; Kowald, Jan; Lindner, Tom H.; Engesser, Marie; Münch, Johannes; Meigen, Christof & Halbritter, Jan
  
• Clinical and Functional Assessment of Digenicity in Renal Phosphate Wasting. Nutrients, 15(9), 2081.
  Petzold, Friederike; Schönauer, Ria; Werner, Andreas & Halbritter, Jan
  
• Delta weight loss unlike genetic variation associates with hyperoxaluria after malabsorptive bariatric surgery. Scientific Reports, 13(1).
  Scherer, Lotte; Schönauer, Ria; Nemitz-Kliemchen, Melanie; Hagemann, Tobias; Hantmann, Elena; de Fallois, Jonathan; Petzold, Friederike; Blüher, Matthias & Halbritter, Jan
  
• Mechanisms of pathogenicity and the quest for genetic modifiers of kidney disease in branchiootorenal syndrome. Clinical Kidney Journal, 17(1).
  Sewerin, Sebastian; Aurnhammer, Charlotte; Skubic, Cene; Blagotinšek, Cokan Kaja; Jeruc, Jera; Rozman, Damjana; Pfister, Frederick; Dittrich, Katalin; Mayer, Brigitte; Schönauer, Ria; Petzold, Friederike & Halbritter, Jan
  
• Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene’s candidacy in 6q16.1 deletions. The American Journal of Human Genetics, 110(6), 998-1007.
  Schönauer, Ria; Jin, Wenjun; Findeisen, Christin; Valenzuela, Irene; Devlin, Laura Alice; Murrell, Jill; Bedoukian, Emma C.; Pöschla, Linda; Hantmann, Elena; Riedhammer, Korbinian M.; Hoefele, Julia; Platzer, Konrad; Biemann, Ronald; Campeau, Philipp M.; Münch, Johannes; Heyne, Henrike; Hoffmann, Anne; Ghosh, Adhideb; Sun, Wenfei ... & Halbritter, Jan
  
• Pathogenic PHIP Variants are Variably Associated With CAKUT. Kidney International Reports, 9(8), 2484-2497.
  de Fallois, Jonathan; Sieckmann, Tobias; Schönauer, Ria; Petzold, Friederike; Münch, Johannes; Pauly, Melissa; Vasileiou, Georgia; Findeisen, Christin; Kampmeier, Antje; Kuechler, Alma; Reis, André; Decker, Eva; Bergmann, Carsten; Platzer, Konrad; Tasic, Velibor; Kirschner, Karin Michaela; Shril, Shirlee; Hildebrandt, Friedhelm; Chung, Wendy K. & Halbritter, Jan
  
• Sex, Genotype, and Liver Volume Progression as Risk of Hospitalization Determinants in Autosomal Dominant Polycystic Liver Disease. Gastroenterology, 166(5), 902-914.
  Schönauer, Ria; Sierks, Dana; Boerrigter, Melissa; Jawaid, Tabinda; Caroff, Lea; Audrezet, Marie-Pierre; Friedrich, Anja; Shaw, Melissa; Degenhardt, Jan; Forberger, Mirjam; de Fallois, Jonathan; Bläker, Hendrik; Bergmann, Carsten; Gödiker, Juliana; Schindler, Philipp; Schlevogt, Bernhard; Müller, Roman-U.; Berg, Thomas; Patterson, Ilse ... & Halbritter, Jan