Proteinuria is an independent risk factor for chronic kidney disease progression and cardiovascular diseases. Apart from its prognostic role, the load of proteins that pass across the disrupted glomerular capillary wall trigger multiple pathophysiologic processes. These include, among others, intratubular complement activation and excessive proximal tubular reabsorption of filtered proteins, especially albumin and albumin-bound free fatty acids, which can set off several pathways of cellular damage. The activation of these pathways can cause apoptosis of proximal tubular cells and paracrine effects that incite the development of interstitial inflammation and fibrosis, ultimately leading to irreversible kidney injury. In this review, we provide a comprehensive overview of the current understanding on the mechanisms underlying the tubular toxicity of ultrafiltered proteins in the setting of proteinuric chronic kidney diseases. The acquired knowledge is expected to be instrumental for the development of novel therapeutic classes of medications to be tested on top of standard of care with optimized renin-angiotensin-aldosterone blockade and sodium-glucose cotransporter-2 inhibition, in order to further improve the clinical outcomes of patients with proteinuric chronic kidney diseases.
Davide Viggiano, Annette Bruchfeld, Sol Carriazo, Antonio De Donato, Nicole Endlich, Ana Carina Ferreira, Andreja Figurek, Denis Fouque, Casper Franssen, Konstantinos Giannakou, Dimitrios Goumenos, Ewout J. Hoorn, Dorothea Nitsch, Alberto Ortíz, Vesna Pešić, Daiva Rastenytė, María José Soler, Merita Rroji, Francesco Trepiccione, Robert J. Unwin, Carsten A. Wagner, Andrzej Więcek, Miriam Zacchia, Carmine Zoccali, Giovambattista Capasso, Giovambattista Capasso, Alexandre Andrade, Maie Bachmann, Inga Arūnė Bumblytė, Adrian Covic, Pilar Delgado, Andreas Engvig, Casper Franssen, Sebastian Frische, Liliana Gârneaţă, Loreto Gesualdo, Konstantinos Giannakou, Ayşe Tuğba Kartal, Laila‐Yasmin Mani, Hans-Peter Marti, Christopher Mayer, Rikke Nielsen, Vesna Pšić, Merita Rroji, Giorgos K. Sakkas, Goce Spasovski, Kate I Stevens, Evgueniy Vazelov, Davide Viggiano, Lefteris C. Zacharia, Ana Carina Ferreira, Jolanta Małyszko, Ewout J. Hoorn, Andreja Figurek, Robert J. Unwin, Carsten A. Wagner, Christoph Wanner, Annette Bruchfeld, Marion Pépin, Andrzej Więcek, Dorothea Nitsch, Ivo Fridolin, Gaye Hafez, María José Soler, Michelangela Barbieri, Bojan Batinić, Laura Carrasco, Ron T. Gansevoort, Gianvito Martino, Francesco Mattace‐Raso, Ionuţ Nistor, Alberto Ortíz, Giuseppe Paolisso, Daiva Rastenytė, Gabriel Ştefan, Gioacchino Tedeschi, Ziad A. Massy, Boris Bikbov, Karlhans Endlich, Olivier Godefroy, Jean‐Marc Chillon, Anastassia Kossioni, Justina Kurganaite, Norberto Perico, Giuseppe Remuzzi, Tomasz Grodzicki, Francesco Trepiccione, Carmine Zoccali, Mustafa Arıcı, Peter J. Blankestijn, Kai‐Uwe Eckardt, Danilo Fliser, Eugenio Gutiérrez Jiménez, Maximilian König, Ivan Rychlík
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