Molecular mechanism explaining albuminuria in kidney disease identified

Prof. Dr. Thomas Benzing

Journal Nature Metabolism - Cover designed by Thomas Phillips Article | 11 May 2020 The biophysical basisi of kidney ultrafiltration.

Human kidneys filter 180 liters of fluid from plasma per day, with almost complete retention of albumin and other macromolecules. Here, the authors used ultraresolution microscopy together with mathematical modelling to provide an experimentally validated model of the kidney filtration barrier. The findings were published in the internationally renowned scientific journal Nature Metabolism - Article | 11 May 2020 with cover: The biophysical basis of kidney ultrafiltration - https://www.nature.com/natmetab/

Mammalian kidneys constantly filter large amounts of liquid, with almost complete retention of albumin and other macromolecules in the plasma. Breakdown of the three-layered renal filtration barrier results in loss of albumin into urine (albuminuria) across the wall of small renal capillaries, and is a leading cause of chronic kidney disease (CKD). In the Western societies CKD is becoming an increasingly prevalent condition affecting almost 10% of the population. The loss of filtration function causes high blood pressure, predisposes to serious cardiovascular disease, stroke and dementia, and can even lead to the need for dialysis. However, exactly how the renal filter works and why its permeability is altered in kidney diseases is poorly understood.

The research group of Prof. Dr. Thomas Benzing, Director of the Dept. for Internal Medicine at the University Hospital of Cologne and the CMMC, has now succeeded in clarifying the function of the kidney filter and showed that the permeability of the renal filter is modulated through compression of the capillary wall.

The research team collected morphometric data prior to and after onset of albuminuria in a mouse model equivalent to a human genetic disease affecting the renal filtration barrier. Combining quantitative analyses with mathematical modelling, they were able to demonstrate that morphological alterations of the glomerular filtration barrier lead to reduced compressive forces that counteract filtration pressure, thereby resulting in capillary dilatation, and ultimately albuminuria. The results reveal distinct functions of the different layers of the filtration barrier and expand the molecular understanding of defective renal filtration in chronic kidney disease.

Linus Butt, the first author of the study, states: “We are all very excited and proud about the progress that was made. The story is the result of a real team effort and I am very proud to be part of the team." The current study was made possible through international cooperation between scientists of the Benzing research group at the Cologne University Hospital and the Center for Molecular Medicine Cologne and the research groups from Boston, Stockholm and Regensburg.

Thomas Benzing comments: "We were surprised by the outcome of the study. The data represent a quantum leap in our understanding of the development of kidney diseases. These results have taken us an important step towards the development of targeted therapies for kidney diseases." The physician-scientist Thomas Benzing is an internationally renowned pioneer in the research of the molecular mechanismes of kidney diseases.

Original publication:
A molecular mechanism explaining albuminuria in kidney disease
Linus Butt, David Unnersjö-Jess, Martin Höhne, Aurelie Edwards, Julia Binz-Lotter, Dervla Reilly, Robert Hahnfeldt, Vera Ziegler, Katharina Fremter, Markus M. Rinschen, Martin Helmstädter, Lena K. Ebert, Hayo Castrop, Matthias J. Hackl, Gerd Walz, Paul T. Brinkkoetter, Max C. Liebau, Kálmán Tory, Peter F. Hoyer, Bodo B. Beck, Hjalmar Brismar, Hans Blom, Bernhard Schermer and Thomas Benzing
https://www.nature.com/articles/s42255-020-0204-yhttps://doi.org/10.1038/s42255-020-0204-y

Please also visit the press release from the University Hospital Cologne:
"Funktion des Nierenfilters geklärt": https://nephrologie.uk-koeln.de/informationen/aktuelles/detailansicht/funktion-des-nierenfilters-geklaert/

Contact
Prof. Dr. Thomas Benzing
Dept. II of Internal Medicine,University Hospital of Cologne and Center for Molecular Medicine Cologne
thomas.benzing[at]uk-koeln.de
http://nephrologie.uk-koeln.de
https://www.kidneyresearchcenter.org/
 

CMMC News Release
Dr. Debora Grosskopf-Kroiher | Center for Molecular Medicine Cologne
debora.grosskopf-kroiher[at]uni-koeln.de