Effect of chronic kidney disease (CKD) on cardiac remodelling. Representative micrographs showing increased cardiomyocyte hypertrophy (left panels), impaired spatial distribution of contrast agent within the left ventricular (LV) wall due to reduced microvascularization (middle panels), and increased myocardial fibrosis as indicated by dark red staining (right panesl) in 5/6 nephrectomized rats (5/6 Nx), an experimental model of CKD, compared with sham-operated animals.

Cardiac and Microvascular Remodeling in CKD

Chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease (CVD), contributing directly to extensive cardiovascular remodeling and damage, beyond the effects of shared conditions like hypertension or diabetes. Common changes include left ventricular hypertrophy, progressive myocardial fibrosis, impaired systolic and diastolic function, and reduced myocardial capillary density. 

Our group has investigated several molecular mechanisms underlying these changes, focusing particularly on the established 5/6 nephrectomy model, which reproduces key features of progressive kidney failure and CKD-associated cardiac remodeling.

One major focus of our work has been the role of fibroblast growth factor 23 (FGF23), a phosphate-responsive hormone. Elevated FGF23 contributes to heart hypertrophy, fibrosis, and impaired function, whereas blocking its signaling can partly reverse these effects.

We have also studied cardiac microcirculation and capillary rarefaction. Our findings show that elevated antiangiogenic factors in CKD, including the soluble vascular endothelial growth factor receptor 1 (sFlt-1), together with impaired repair mechanisms, contribute to structural and functional cardiac injury. 

 

Related publications:

Di Marco GS, Brand M. Off-target effects and adverse outcomes of fibroblast growth factor 23 in chronic kidney disease. Port J Nephrol Hypert. 2018; 32(1):57-63. 

Golle L, Gerth HU, Beul K, Heitplatz B, Barth P, Fobker M, Pavenstädt H, Di Marco GS, Brand M. Bone marrow-derived cells and their conditioned medium induce microvascular repair in uremic rats by stimulation of endogenous repair mechanisms.Sci Rep. 2017; 7(1):9444. 

Grabner A, Schramm K, Silswal N, Hendrix M, Yanucil C, Czaya B, Singh S, Wolf M, Hermann S, Stypmann J, Di Marco GS, Brand M, Wacker MJ, Faul C. FGF23/FGFR4-mediated left ventricular hypertrophy is reversible.Sci Rep. 2017; 7(1):1993. 

Singh S, Grabner A, Yanucil C, Schramm K, Czaya B, Krick S, Czaja MJ, Bartz R, Abraham R, Di Marco GS, Brand M, Wolf M, Faul C. Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease.Kidney Int. 2016; 90(5):985-996.

Phosphatregulation und kardiovaskuläre Konsequenzen – Was ist bei chronisch nierenerkrankten Patienten zu beachten? Brand M, Di Marco GS, Pavenstädt H. Dialyse aktuell 2015;19(S01):s6-s10

Grabner A, Amaral AP, Schramm K, Singh S, Sloan A, Yanucil C, Li J, Shehadeh LA, Hare JM, David V, Martin A, Fornoni A, Di Marco GS, Kentrup D, Reuter S, Mayer AB, Pavenstädt H, Stypmann J, Kuhn C, Hille S, Frey N, Leifheit-Nestler M, Richter B, Haffner D, Abraham R, Bange J, Sperl B, Ullrich A, Brand M, Wolf M, Faul C. Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy.Cell Metab. 2015;22(6):1020-1032. 

Di Marco GS, Kentrup D, Reuter S, Mayer AB, Golle L, Tiemann K, Fobker M, Engelbertz C, Breithardt G, Brand E, Reinecke H, Pavenstädt H, Brand M. Soluble Flt-1 links microvascular disease with heart failure in CKD.Basic Res Cardiol. 2015; 110(3):30. 

Di Marco GS, Reuter S, Kentrup D, Grabner A, Amaral AP, Fobker M, Stypmann J, Pavenstädt H, Wolf M, Faul C, Brand M. Treatment of established left ventricular hypertrophy with fibroblast growth factor receptor blockade in an animal model of CKD. Nephrol Dial Transplant. 2014; 29(11):2028-2035. 

Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, Gutiérrez OM, Aguillon-Prada R, Lincoln J, Hare JM, Mundel P, Morales A, Scialla J, Fischer M, Soliman EZ, Chen J, Go AS, Rosas SE, Nessel L, Townsend RR, Feldman HI, St John Sutton M, Ojo A, Gadegbeku C, Di Marco GS, Reuter S, Kentrup D, Tiemann K, Brand M, Hill JA, Moe OW, Kuro-O M, Kusek JW, Keane MG, Wolf M. FGF23 induces left ventricular hypertrophy.J Clin Invest. 2011;121(11):4393-408. 

Di Marco GS*, Reuter S*, Kentrup D, Ting L, Ting L, Grabner A, Jacobi AM, Pavenstädt H, Baba HA, Tiemann K, Brand M. Cardioprotective effect of calcineurin inhibition in an animal model of renal disease. Eur Heart J. 2011;32(15):1935-45.

Di Marco GS, Reuter S, Hillebrand U, Amler S, König M, Larger E, Oberleithner H, Brand E, Pavenstädt H, Brand M. Soluble VEGF receptor Flt1 (sFlt-1) contributes to endothelial dysfunction in chronic kidney disease. J Am Soc Nephrol. 2009;20(10):2235-45.