Else Kröner-Fresenius-Zentrum (EKFZ)

During ageing acquired somatic mutations in cells of the hematopoietic system accumulate. Somatic mutations within autosomal genes, termed clonal hematopoiesis of indeterminate potential (CHIP), emerged as an important driver of cardiovascular diseases (CVD). Recently, mosaic loss of the Y chromosome (LOY) in hematopoietic cells has been identified to promote diffuse cardiac fibrosis. We aim to understand the mechanisms leading to the development of somatic mutations, their effects on initiation and progression of cardiorenal disease, as well as the interaction betweeen cells harboring somatic mutations with the tissue microenvironment.

Key publications

Loss of Y Chromosome and Cardiovascular Events in Chronic Kidney Disease.
Weyrich M, Cremer S, Gerster M, Sarakpi T, Rasper T, Zewinger S, Patyna SR, Leistner DM, Heine GH, Wanner C, März W, Fliser D, Dimmeler S, Zeiher AM, Speer T. 
Circulation. 2024

Sterile inflammation triggered by the activation of the innate immune system represents a crucial driver of cardiorenal disease. Thereby, the NLRP3 inflammasome, a multimeric cytosolic protein complex mediating maturation of IL-1b, plays a particular role. Life-long genetically mediated NLRP3 inflammasome activation associates with higher cardiovascular mortality, which underscores the role of inflammation in cardiovascular disease. We aim to understand the specific contribution of sterile inflammation to the development of CVD and CKD, and on how this can be therapeutically targeted

Key publications

Targeting innate immunity-driven inflammation in CKD and cardiovascular disease.
Speer T, Dimmeler S, Schunk SJ, Fliser D, Ridker PM. 
Nat Rev Nephrol. 2022

Interleukin-1α Is a Central Regulator of Leukocyte-Endothelial Adhesion in Myocardial Infarction and in Chronic Kidney Disease.
Schunk SJ, Triem S, Schmit D, Zewinger S, Sarakpi T, Becker E, Hütter G, Wrublewsky S, Küting F, Hohl M, Alansary D, Prates Roma L, Lipp P, Möllmann J, Lehrke M, Laschke MW, Menger MD, Kramann R, Boor P, Jahnen-Dechent W, März W, Böhm M, Laufs U, Niemeyer BA, Fliser D, Ampofo E, Speer T. 
Circulation. 2021

Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality.
Schunk SJ, Kleber ME, März W, Pang S, Zewinger S, Triem S, Ege P, Reichert MC, Krawczyk M, Weber SN, Jaumann I, Schmit D, Sarakpi T, Wagenpfeil S, Kramann R, Boerwinkle E, Ballantyne CM, Grove ML, Tragante V, Pilbrow AP, Richards AM, Cameron VA, Doughty RN, Dubé MP, Tardif JC, Feroz-Zada Y, Sun M, Liu C, Ko YA, Quyyumi AA, Hartiala JA, Tang WHW, Hazen SL, Allayee H, McDonough CW, Gong Y, Cooper-DeHoff RM, Johnson JA, Scholz M, Teren A, Burkhardt R, Martinsson A, Smith JG, Wallentin L, James SK, Eriksson N, White H, Held C, Waterworth D, Trompet S, Jukema JW, Ford I, Stott DJ, Sattar N, Cresci S, Spertus JA, Campbell H, Tierling S, Walter J, Ampofo E, Niemeyer BA, Lipp P, Schunkert H, Böhm M, Koenig W, Fliser D, Laufs U, Speer T; eQTLGen consortium; BIOS consortium. 
Eur Heart J. 2021

Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation.
Zewinger S, Reiser J, Jankowski V, Alansary D, Hahm E, Triem S, Klug M, Schunk SJ, Schmit D, Kramann R, Körbel C, Ampofo E, Laschke MW, Selejan SR, Paschen A, Herter T, Schuster S, Silbernagel G, Sester M, Sester U, Aßmann G, Bals R, Kostner G, Jahnen-Dechent W, Menger MD, Rohrer L, März W, Böhm M, Jankowski J, Kopf M, Latz E, Niemeyer BA, Fliser D, Laufs U, Speer T. 
Nat Immunol. 2020

For decades, immunological memory was thought to be a hallmark of the adaptive immune response, differentiating adaptive from innate immunity. However, this concept has been challenged through the identification of innate immune reprogramming or trained immunity. Stimulation of hematopoietic progenitors by proinflammatory stimuli induces long-lasting epigenetic and metabolic alterations in the hematopoietic compartment, which leads to an augmented inflammatory response upon re-stimulation. We aim to understand on how chronic kidney disease induces hematopoietic reprogramming and on how this affects secondary cardiovascular injury. Moreover, we explore the role of trained innate immunity in the development of cardiovascular injury after solid organ transplantation.

Key publications

Targeting innate immunity-driven inflammation in CKD and cardiovascular disease.
Speer T, Dimmeler S, Schunk SJ, Fliser D, Ridker PM. 
Nat Rev Nephrol. 2022

Fibrosis represents a common denominator of all types of kidney diseases. The evolutionary conserved Wnt/b-catenin signaling pathway plays a pivotal role in the development of kidney fibrosis and injury. DKK3 represents an important regulator of this pathway. During kidney injury DKK3 released into the urine, where it can be quantified. We found that quantification of DKK3 in the urine allows identification of patients at short-term risk of CKD progression, the transition of acute kidney injury into CKD, as well as patients who particularly benefit from preventive therapeutic strategies.

Key publications

Urinary DKK3 as a biomarker for short-term kidney function decline in children with chronic kidney disease: an observational cohort study.
Speer T, Schunk SJ, Sarakpi T, Schmit D, Wagner M, Arnold L, Zewinger S, Azukaitis K, Bayazit A, Obrycki L, Kaplan Bulut I, Duzova A, Doyon A, Ranchin B, Caliskan S, Harambat J, Yilmaz A, Alpay H, Lugani F, Balat A, Arbeiter K, Longo G, Melk A, Querfeld U, Wühl E, Mehls O, Fliser D, Schaefer F; 4C Study Investigators, ESCAPE Trial Investigators. 
Lancet Child Adolesc Health. 2023

Measurement of urinary Dickkopf-3 uncovered silent progressive kidney injury in patients with chronic obstructive pulmonary disease.
Schunk SJ, Beisswenger C, Ritzmann F, Herr C, Wagner M, Triem S, Hütter G, Schmit D, Zewinger S, Sarakpi T, Honecker A, Mahadevan P, Boor P, Wagenpfeil S, Jörres R, Watz H, Welte T, Vogelmeier CF, Gröne HJ, Fliser D, Bals R, Speer T. 
Kidney Int. 2021

WNT-β-catenin signalling - a versatile player in kidney injury and repair.
Schunk SJ, Floege J, Fliser D, Speer T. 
Nat Rev Nephrol. 2021

Dickkopf 3-a novel biomarker of the 'kidney injury continuum'.
Schunk SJ, Speer T, Petrakis I, Fliser D. 
Nephrol Dial Transplant. 2021

Association between urinary dickkopf-3, acute kidney injury, and subsequent loss of kidney function in patients undergoing cardiac surgery: an observational cohort study.
Schunk SJ, Zarbock A, Meersch M, Küllmar M, Kellum JA, Schmit D, Wagner M, Triem S, Wagenpfeil S, Gröne HJ, Schäfers HJ, Fliser D, Zewinger S, Speer T. 
Lancet. 2019

Dickkopf-3 (DKK3) in Urine Identifies Patients with Short-Term Risk of eGFR Loss.
Zewinger S, Rauen T, Rudnicki M, Federico G, Wagner M, Triem S, Schunk SJ, Petrakis I, Schmit D, Wagenpfeil S, Heine GH, Mayer G, Floege J, Fliser D, Gröne HJ, Speer T. 
J Am Soc Nephrol. 2018