Acute kidney injury and chronic kidney disease: From the laboratory to the clinic

Abstract

Chronic kidney disease and acute kidney injury have traditionally been considered as separate entities with different etiologies. This view has changed in recent years, with chronic kidney disease recognized as a major risk factor for the development of new acute kidney injury, and acute kidney injury now accepted to lead to de novo or accelerated chronic and end stage kidney diseases. Patients with existing chronic kidney disease appear to be less able to mount a complete 'adaptive' repair after acute insults, and instead repair maladaptively, with accelerated fibrosis and rates of renal functional decline. This article reviews the epidemiological studies in man that have demonstrated the links between these two processes. We also examine clinical and experimental research in areas of importance to both acute and chronic disease: acute and chronic renal injury to the vasculature, the pericyte and leukocyte populations, the signaling pathways implicated in injury and repair, and the impact of cellular stress and increased levels of growth arrested and senescent cells. The importance and therapeutic potential raised by these processes for acute and chronic injury are discussed.

Keywords: Cell cycle arrest; Fibrosis; Kidney microvasculature; Kidney repair; Senescence.

Figure 1. Chronic kidney disease and maladaptive repair after acute kidney injury

A kidney with chronic kidney disease is less likely to undergo complete adaptive repair after an acute renal insult. In the context of pre-injury fibrosis, senescence and microvascular loss the kidney is more likely to repair maladaptively with increased tubular loss and scarring. While a normal kidney can respond to injury with adaptive repair it is also recognized that with greater levels of injury and increasing age maladaptive repair to CKD is more likely.

Figure 2. Inter-related features of chronic kidney disease and acute kidney injury

Features seen in chronic kidney disease are shown on the left and acute kidney injury on the right. Solid lines demonstrate well established connections between these features, with dotted lines indicating suspected or proposed connections.

Figure 3. Cell cycle progression in acute and chronic kidney disease

Studies of models of renal injury have detected cells arrested at the G2/M checkpoint that secrete pro-fibrotic factors promoting maladaptive repair and the transition from acute to chronic kidney disease. Cell cycle arrest can also occur in the G1/S phase resulting in p16^INK4a positive senescent cells which, via the senescence-associated secretory phenotype (SASP), also promote changes in aged and injured kidneys.