A conceptual framework for the molecular pathogenesis of progressive kidney disease

Abstract

The data regarding the pathogenesis of progressive kidney disease implicate cytokine effects, physiological factors, and myriad examples of relatively nonspecific cellular dysfunction. The sheer volume of information being generated on this topic threatens to overwhelm our efforts to understand progression in chronic kidney disease or to derive rational strategies to treat it. Here, a conceptual framework is offered for organizing and considering these data. Disease is initiated by an injury that evokes a tissue-specific cellular response. Subsequent structural repair may be effective, or the new structure may be sufficiently changed that it requires an adaptive physiological response. If this adaptation is not successful, subsequent cycles of misdirected repair or maladaptation may lead to progressive nephron loss. To illustrate how this framework can be used to organize our approach to disease pathogenesis, the role of cytokines in proteinuria and progressive glomerular disease is discussed. Finally, this theoretical framework is reconsidered to examine its implications for the diagnosis and treatment of clinical conditions. Application of this schema could have significant relevance to both research inquiry and clinical practice.

Fig. 1

Theoretical schema for the pathogenesis of chronic kidney disease. ECM Extracellular matrix. See text for details

Fig. 2

Steps in the development of chronic kidney disease (CKD) secondary to idiopathic focal segmental glomerulosclerosis (FSGS). An initial wave of cytokines, representing the injury (genetic and/or environmental) and response stages of disease pathogenesis, leads to proteinuria. Different mechanisms affecting cytoskeletal/slit diaphragm integrity may mediate proteinuria. For those that cause sufficient injury, a repair process is initiated, with a second wave of cytokine expression. If this repair is not physiologically controlled, a maladaptive state leads to a chronic cycle of injury and misdirected repair, leading to death and structural loss in the process of scar formation. In contrast, minimal change disease (MCD) involves only the left-hand part of the diagram, from cytokines to proteinuria. SNGFR Single nephron glomerular filtration rate

Fig. 3

Stages of progressive kidney disease. Using idiopathic FSGS as an example, temporal/functional relationships are shown among clinical status, pathogenetic stage according to the conceptual construct proposed in this essay, the phase of the clinical disease, and some of the factors that contribute to progression in the different stages of the disease. Resistant FSGS refers to the stage at which the disease is relatively resistant to standard forms of therapy for glomerular disease. Please note that a similar table could be prepared, for example, to describe the status of a patient who has nephron loss from polycystic kidney disease