Immune mechanisms in the different phases of acute tubular necrosis

Abstract

Acute kidney injury is a clinical syndrome that can be caused by numerous diseases including acute tubular necrosis (ATN). ATN evolves in several phases, all of which are accompanied by different immune mechanisms as an integral component of the disease process. In the early injury phase, regulated necrosis, damage-associated molecular patterns, danger sensing, and neutrophil-driven sterile inflammation enhance each other and contribute to the crescendo of necroinflammation and tissue injury. In the late injury phase, renal dysfunction becomes clinically apparent, and M1 macrophage-driven sterile inflammation contributes to ongoing necroinflammation and renal dysfunction. In the recovery phase, M2-macrophages and anti-inflammatory mediators counteract the inflammatory process, and compensatory remnant nephron and cell hypertrophy promote an early functional recovery of renal function, while some tubules are still badly injured and necrotic material is removed by phagocytes. The resolution of inflammation is required to promote the intrinsic regenerative capacity of tubules to replace at least some of the necrotic cells. Several immune mechanisms support this wound-healing-like re-epithelialization process. Similar to wound healing, this response is associated with mesenchymal healing, with a profound immune cell contribution in terms of collagen production and secretion of profibrotic mediators. These and numerous other factors determine whether, in the chronic phase, persistent loss of nephrons and hyperfunction of remnant nephrons will result in stable renal function or progress to decline of renal function such as progressive chronic kidney disease.

Keywords: Acute kidney injury; Extracellular traps; Injury; Necroptosis; Therapeutics.

Figure 1. The immune system during homeostasis and necroinflammation

(A) Renal resident mononuclear phagocytes originate from the yolk sac during nephrogenesis. (B, C) These cells or the bone marrow scatter around the tubular basement membrane throughout the entire nephron. (B) Infiltrating mononuclear phagocytes originate from the bone marrow and follow chemokine tracks to the injured kidney. During necroinflammation (D), both resident and infiltrating immune cells react to danger-associated molecular patterns (DAMPs) released by dying tubular cells. By releasing more alarmins and DAMPs, further immunogenic cell death is induced, and more immune cells are attracted from the bone marrow via the circulation.

Figure 2. Acute kidney injury and renal inflammation

A general misconception is that the current classification of acute kidney injury (AKI) is not based on markers of tubular necrosis but on markers of renal function. In fact, not the clinical representation of declined renal function, but only severity assessment of the underlying mechanisms of ATN serves as a reliable predictor of AKI-to-chronic kidney disease (CKD) progression. This becomes even more evident for unilateral forms of kidney injury, because serum creatinine (SCr) and urinary output usually remain unaffected in patients with normal baseline glomerular filtration rate (GFR). Nevertheless, some forms of unilateral acute kidney disease involve true kidney injury, renal inflammation, and necrosis such as unilateral renal embolism and thereby cover all phases of renal injury and regeneration. The concept of distinct phases of ATN is an extension of ideas by Sutton et al [10] and Okusa and Chertow [11]. The drop and recovery of GFR and the increase in SCr level are shown along the course of an AKI episode. The suggested course of AKI assumes that the trigger for injury was transient and not repetitive or persistent, either unilateral or bilateral. The immunological characterization of each underlying phase of acute tubular necrosis (ATN; A–E) is described in detail in the text. KDIGO, Kidney Disease Improving Global Outcomes.