Center for Molecular Medicine Cologne

Liebau, Max C | Schermer, Bernhard C 11

Understanding the mechanisms underlying early kidney failure in ARPKD


Polycystic kidney diseases (PKD) affect millions of people worldwide and are the major genetic cause of kidney replacement therapy (KRT) in both children and adults. The two major types of PKD are the more common autosomal-dominant polycystic kidney disease (ADPKD), mainly caused by variants in the PKD genes PKD1 and PKD2, and the rare pediatric autosomal-recessive polycystic kidney disease (ARPKD), mainly caused by PKHD1 variants. Notably, there is clinical and genetic overlap between ARPKD and ADPKD. All three genes encode for proteins localized to primary cilia. Cilia are sensory organelles that in the kidney project from the apical membrane of epithelial cells into the lumen of the tubules. PKD is generally regarded as a paradigm ciliopathy. In contrast to ADPKD, for which a first disease-modifying pharmacological therapy has been established, there is currently no targeted therapy for ARPKD.
PKHD1 encodes for the large ciliary transmembrane protein fibrocystin (FC). Disease-causing variants in PKHD1 have been described almost across the entire gene. By analyzing longitudinal clinical data of hundreds of ARPKD patients in a large multinational collaborative effort, we could recently gain significant insights into the genotype-phenotype correlation of ARPKD patients. We could show that missense variants in specific areas of the gene are associated with better kidney survival. With the ARegPKD registry initiated by one of the applicants, we have full access to the largest clinical ARPKD database worldwide. Moreover, we could generate and confirm the recently described first Pkhd1-associated preclinical model of ARPKD that results in a kidney and liver phenotype recapitulating human ARPKD. Using a translational approach by combining our novel insights into genotype-phenotype correlations with available with the novel mammalian in vivo model, we follow the overarching aim to uncover the mechanisms of how variants in Pkhd1 result in PKD by affecting primary cilia and transcriptional programs in kidney cells. In particular, we aim to understand why variants affecting some parts of FC result in rapid progression of kidney disease while others affect kidneys much later in life. Specifically, we will (1) analyze on the cellular level how individual missense variants in Pkhd1 affect FC function and the transcriptome of kidney epithelial cells, (2) investigate FC-related regulation of the ciliary protein composition in vitro and in vivo, and (3) study how missense and null variants in PKHD1/Pkhd1 affect cell type specific signaling in kidneys. Ultimately, we aim to contribute to the development of novel disease-modifying therapeutic concepts for ARPKD.

Clinical Relevance

Autosomal-recessive polycystic kidney disease (ARPKD) is a severe and early-onset pediatric disease characterized by fibrocystic changes in kidneys and the liver. It is a major cause of chronic kidney disease and kidney failure in children requiring dialysis or transplantation. There is no targeted therapy yet as the molecular pathogenesis is not well understood. Here, we aim to combine the power of clinical knowledge obtained from a pan-European registry study with state-of-the-art preclinical models, cellular biochemical approaches, and single-cell transcriptomics to identify the relevant pathways that distinguish between early and late renal involvement. We anticipate that our work will result in a deeper disease understanding paving the way for strategies to delay the onset and progression of kidney disease in ARPKD and additional renal ciliopathies.


Overall approach of the suggested project

Kidney findings in ARPKD and research questions of the project


  1. Mekahli D*, Liebau MC*, Cadnapaphornchai MA, Goldstein SL, Greenbaum LA, Litwin M, Seeman T, Schaefer F, Guay-Woodford LM. (*shared first authorship) „Design of two ongoing clinical trials of tolvaptan in the treatment of pediatric patients with autosomal recessive polycystic kidney disease“. BMC Nephrology 2023 Feb 13;24(1):33. doi: 10.1186/s12882-023-03072-x.
  2. Kieckhöfer E, Slaats GG, Ebert LK, Albert MC, Dafinger C, Kashkar H, Benzing T, Schermer B. „Primary cilia suppress Ripk3-mediated necroptosis.“ Cell Death Discovery. 2022 Dec 2;8(1):477. doi: 10.1038/s41420-022-01272-2.
  3. Liebau MC, Hartung EA, Perrone RD „Perspectives on Drug Development in Autosomal Recessive Polycystic Kidney Disease“ Clinical Journal of the American Society of Nephrology. 2022 Oct;17(10):1551-1554. doi: 10.2215/CJN.04870422. Epub 2022 Aug 23.
  4. Ajiri R, Burgmaier K, Akinci N, Broekaert I, Büscher A, Dursun I, Duzova A, Eid LA, Fila M, Gessner M, Gokce I, Massella L, Mastrangelo A, Miklaszewska M, Prikhodina L, Ranchin B, Ranguelov N, Rus R, Sever L, Thumfart J, Weber LT, Wuehl E, Yilmaz A, Dötsch J, Schaefer F, Liebau MC. „Phenotypic Variability in Siblings with Autosomal Recessive Polycystic Kidney Disease”. Kidney International Reports, 2022 May 4;7(7):1643-1652. doi: 10.1016/j.ekir.2022.04.095. eCollection 2022 Jul.
  5. Burgmaier K, KilianS, Arbeiter K, Atmis B, Büscher A, Derichs U, Dursun I, Duzova A, Eid LA, Galiano M, Gessner M, Gokce I, Haeffner K, Hooman N, Jankauskiene A, Körber F, Longo G, Massella L, Mekahli D, Miloševski-Lomić G, Nalcacioglu H, Rus R, Shroff R, Stabouli S, Weber LT, Wygoda S, Yilmaz A, Zachwieja K, Zagozdzon I, Dötsch J, Schaefer F, Liebau MC & the ARegPKD consortium. ”Early childhood height-adjusted total kidney volume as a risk marker of kidney survival in ARPKD”. Scientific Reports 2021 Nov 4;11(1):21677. doi: 10.1038/s41598-021-00523-z.
  6. Burgmaier K, Brinker L, Erger F, Beck B, Benz M, Bergmann C, Boyer O, Collard L, Dafinger C, Fila M, Kowalewska C, Lange-Sperandio B, Massella L, Mastrangelo A, Mekahli D, Miklaszewska M, Ortiz-Bruechle N, Patzer L, Prikhodina L, Ranchin B, Ranguelov N, Schild R, Seeman T, Sever L, Sikora P, Szczepanska M, Teixeira A, Thumfart J, Uetz B, Weber LT, Wühl E, Zerres K, ESCAPE Study group, GPN study group, Dötsch J, Schaefer F, Liebau MC for the ARegPKD consortium. “Refining genotype-phenotype correlations in 304 patients with autosomal recessive polycystic kidney disease (ARPKD) and PKHD1 variants”. Kidney International 2021 Sep;100(3):650-659. doi: 10.1016/j.kint.2021.04.019.
  7. Schlingmann KP, Jouret F, Shen K, Nigam A, Arjona FJ, Dafinger C, Houillier P, Jones DP, Kleinerüschkamp F, Oh J, Godefroid N, Eltan M, Güran T, Burtey S, Parotte MC, König J, Braun A, Bos C, Ibars Serra M, Rehmann H, Zwartkruis FJT, Renkema KY, Klingel K, Schule-Bahr E, Schermer B, Bergmann C, Altmüller J, Thiele H, Beck BB, Dahan K, Sabatini D, Liebau MC, Vargas-Poussou R, Knoers NVAM, Konrad M, de Baaij JHF. „mTOR-Activating Mutations in RRAGD Are Causative for Kidney Tubulopathy and Cardiomyopathy“ Journal of the American Society of Nephrology, 2021 Nov;32(11):2885-2899. doi: 10.1681/ASN.2021030333.
  8. Dafinger C, Mandel AM, Braun A, Göbel H, Burgmaier K, Massella L, Mastrangelo A, Dötsch J, Benzing T, Weimbs T, Schermer BLiebau MC. „The carboxy-terminus of the human ARPKD protein fibrocystin can control STAT3 signalling by regulating SRC-activation“; Journal of Cellular and Molecular Medicine, 2020 Dec;24(24):14633-14638. doi: 10.1111/jcmm.16014.
  9. Butt L, Unnersjö-Jess D, Höhne M, Edwards A, Binz-Lotter J, Reilly D, Hahnfeldt R, Ziegler V, Fremter K, Rinschen MM, Helmstädter M, Ebert LK, Castrop H, Hackl MJ, Walz G, Brinkkoetter PT, Liebau MC, Tory K, Hoyer PF, Beck BB, Brismar H, Blom H, Schermer B, Benzing T. „A molecular mechanism explaining albuminuria in kidney disease“ Nature Metabolism 2020 May;2(5):461-474. doi: 10.1038/s42255-020-0204-y. 
  10. AkarkachA, Burgmaier K, Sander A, Hooman N, Sever L, CanoF, Zambrano P, Bilge I, Flynn JT, Yavascan O, Vallés PG, Munarriz RL, PatelHP, Serdaroglu E, Koch VH, del Carmen Suarez A, Galanti M, Gonzalez Celedon C, Rébori A, KariJA, Wong CJ, Elenberg E, Rojas LF, Warady BA, Liebau MC*, Schaefer F* for the IPPN registry *shared last authorship; „Maintenance peritoneal dialysis in children with Autosomal Recessive Polycystic Kidney Disease: A comparative cohort study of the international pediatric peritoneal dialysis network registry”, American Journal of Kidney Disease, 2020 Mar;75(3):460-464. doi: 10.1053/j.ajkd.2019.10.009. Epub 2020 Jan 23.
  11. Dafinger C, Rinschen MM, Borgal L, Ehrenberg C, Basten SG, Franke M, Höhne M, Rauh M, Göbel H, Wunderlich FT, Peters DJM, Tasche D, Mishra T, Habbig S, Dötsch J, Müller RU, Brüning JC, Persigehl T, Giles RH, Benzing T, Schermer B*Liebau MC*. *shared last authorship “Targeted deletion of the AAA-ATPase Ruvbl1 in mice disrupts ciliary integrity and causes renal disease and hydrocephalus”; Experimental Molecular Medicine. 2018 Jun 28;50(6):75.
  12. Kohli P, Höhne M, Jüngst C, Bertsch S, Ebert LK, Schauss AC, Benzing T, Rinschen MM, Schermer B. „The ciliary membrane-associated proteome reveals actin-binding proteins as key components of cilia“. EMBO Reports. 2017 Sep;18(9):1521-1535. doi: 10.15252/embr.201643846. Epub 2017 Jul 14.

Clinical Relevance

  1. Burgmaier K, Broekaert IJ, Liebau MC „Autosomal Recessive Polycystic Kidney Disease: Diagnosis, Prognosis and Management“ Advances in Kidney Disease and Health ACKD-D-22-00049R1 (in press).
  2. Liebau MC, Hartung EA, Perrone RD „Perspectives on Drug Development in Autosomal Recessive Polycystic Kidney Disease“ Clinical Journal of the American Society of Nephrology. 2022 Oct;17(10):1551-1554. doi: 10.2215/CJN.04870422. Epub 2022 Aug 23.
  3. Liebau MC. „Early clinical management of autosomal recessive polycystic kidney disease“ Pediatric Nephrology. 2021 Nov;36(11):3561-3570. doi: 10.1007/s00467-021-04970-8.  


Prof. Dr. Max C Liebau CMMC Cologne
Prof. Dr. Max C Liebau

Clinic and Polyclinic for Pediatric and Adolescent Medicine

CMMC - PI - C 11

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Claudia Dafinger
Kathrin Burgmaier

Jopp Hillen
Büsra Yildirim