MO1032HISTORY OF THE PARADIGMS OF INFLAMMATION IN KIDNEY DISEASES
Authors: Viggiano Davide , Capasso Giovambattista 
Published: May 2021

Abstract

Background and Aims
The term "inflammation" is undoubtedly one of the oldest medical terms and yet in use. However, its meaning has changed over the centuries. This work gives a historical and critical view of the concept of inflammation, with particular reference to kidney diseases.

Method
The term "inflammation" was used in Galenic medicine to specify a collection of symptoms. Celsus (c. 25 BC – c. 50 AD) described "rubor et tumor cum calor et dolor", but the list became much longer in subsequent Galenic scholars. It is interesting to note that one of the inflammation symptoms, "tumor," was then used to indicate cancer (tumor=swelling due to a mass or due to edema). Virchow (1821 –1902) is often quoted for introducing a fifth symptom, "function Lasa", but his significant contribution relies on introducing the microscope to study diseases: thanks to this instrument, the paradigm of inflammation was undergoing a revolution. Thereby, the definition of inflammation shifted from a pure collection of symptoms to a histopathological classification, characterized by the tissue "inflammatory infiltrates" with subcategories according to the cell types involved. Numerous authors added their names to pathology textbooks when describing a new kind of cellular infiltration.
Overall, the tremendous success of the histopathologic paradigm of inflammation or "inflammatory infiltrates" was the possibility to contain and revert this phenomenon with corticosteroids (with few exceptions). Subsequently, specific drugs were proposed for each inflammatory infiltrate. This type of paradigm is still used today to define, e.g., tubulointerstitial nephritis or intra- and peri-glomerular inflammations. The subsequent classification of inflammatory infiltrates using immunohistochemistry did not modify our classification system (the distinction of, e.g., CD20 lymphocytes from CD4 T-cells is not used, unfortunately, in today's classification system).

Results
Towards the 1940s, Avery et al. recognize that some plasma proteins (specifically the famous C-reactive protein) increase during acute infection, which is a typical inflammatory state. This observation led to a new "molecular definition of inflammation". The idea to identify the presence of inflammatory infiltrates in tissues just by looking at plasma constituents had great success: after all, the histological processing of tissues was no longer needed. Even though many authors were alerting that these plasma constituents are often increased even in the absence of any "inflammatory infiltrate", the plasma proteins were so easily accessible that the new direction was not modifiable.
A modern generalization of this type of approach is called "liquid biopsy, " even though it is not limited to the inflammatory states, but to a larger number of identifiable diseases today only histologically.
The effect of the new "molecular" definition of inflammation was that a large number of diseases without significant inflammatory infiltrates (such as obesity, atherosclerosis, aging, dialysis, and chronic kidney disease) are notwithstanding accompanied by the increase of plasma proteins labeled as "inflammatory". Therefore, the list of "inflammatory" diseases (in the new terms) is now much more extensive. The price for such enlargement of conditions is that most new entries do not respond to steroids or other anti-inflammatory drugs.

Conclusion
The new definition of" inflammatory disease" comprises classical steroid-dependent disorders characterized by inflammatory infiltrates and new conditions with minimal inflammatory infiltrates plus the presence of "inflammatory" plasma proteins plus little response to steroids. It might be beneficial to distinguish these types of inflammation.