Progression after AKI: Understanding Maladaptive Repair Processes to Predict and Identify Therapeutic Treatments

Abstract

Recent clinical studies indicate a strong link between AKI and progression of CKD. The increasing prevalence of AKI must compel the nephrology community to consider the long-term ramifications of this syndrome. Considerable gaps in knowledge exist regarding the connection between AKI and CKD. The 13th Acute Dialysis Quality Initiative meeting entitled "Therapeutic Targets of Human Acute Kidney Injury: Harmonizing Human and Experimental Animal Acute Kidney Injury" convened in April of 2014 and assigned a working group to focus on issues related to progression after AKI. This article provides a summary of the key conclusions and recommendations of the group, including an emphasis on terminology related to injury and repair processes for both clinical and preclinical studies, elucidation of pathophysiologic alterations of AKI, identification of potential treatment strategies, identification of patients predisposed to progression, and potential management strategies.

Keywords: acute renal failure; chronic renal; disease; fibrosis; progression of renal failure.

Figure 1.

Conceptual illustration of events after a renal insult. The ongoing events of injury and repair represent possible scenarios in which the degree of injury and established repair potential contribute to resolution or progression, with red lines indicating the injury and green lines representing repair activity. (A) Subclinical AKI with adaptive repair, in which injury reaches threshold levels of damage markers (i.e., KIM-1) but is lower than functional markers (i.e., changes in creatinine). Repair matches the injury, resulting in adaptive repair. (B) A greater level of injury increases both damage and functional markers, resulting in clinical AKI, and repair activity matches injury, leading to complete resolution. (C) Repair activity is overwhelmed by injury, and fibrosis develops (orange), leading to chronic damage and nonrecovery with higher levels of damage and functional markers than at the start. (D) The development of two episodes of injury superimposed on underlying CKD, with the biomarker levels starting above the threshold of significance. As the first injury is being repaired, there is a second insult, which occurs before completion of repair. The two shades of orange and brown represent the contributions of the original injury and the second insult, respectively, toward maladaptive repair and fibrosis. The fibrotic response is exacerbated, because repair mechanisms are already exhausted, and additional injury results in greater separation between the two processes. The horizontal line at which the repair ends is much higher than the start, representing the decrease in function and a higher creatinine level.