From Acute to Chronic: Unraveling the Pathophysiological Mechanisms of the Progression from Acute Kidney Injury to Acute Kidney Disease to Chronic Kidney Disease

Abstract

This article provides a thorough overview of the biomarkers, pathophysiology, and molecular pathways involved in the transition from acute kidney injury (AKI) and acute kidney disease (AKD) to chronic kidney disease (CKD). It categorizes the biomarkers of AKI into stress, damage, and functional markers, highlighting their importance in early detection, prognosis, and clinical applications. This review also highlights the links between renal injury and the pathophysiological mechanisms underlying AKI and AKD, including renal hypoperfusion, sepsis, nephrotoxicity, and immune responses. In addition, various molecules play pivotal roles in inflammation and hypoxia, triggering maladaptive repair, mitochondrial dysfunction, immune system reactions, and the cellular senescence of renal cells. Key signaling pathways, such as Wnt/β-catenin, TGF-β/SMAD, and Hippo/YAP/TAZ, promote fibrosis and impact renal function. The renin-angiotensin-aldosterone system (RAAS) triggers a cascade leading to renal fibrosis, with aldosterone exacerbating the oxidative stress and cellular changes that promote fibrosis. The clinical evidence suggests that RAS inhibitors may protect against CKD progression, especially post-AKI, though more extensive trials are needed to confirm their full impact.

Keywords: acute kidney disease; acute kidney injury; biomarker; chronic kidney disease.

Figure 1

Mechanism involved in the transition from acute kidney injury to chronic kidney disease. Abbreviation: CKD, chronic kidney disease.

Figure 2

(1) Under normal conditions, in the absence of Wnt ligand interactions, LRP contributes to the phosphorylation of β-catenin, resulting in its retention in the cytoplasm. However, during pathological processes, Wnt ligands bind to the FZD/LRP complex, leading to the prevention of β-catenin phosphorylation. This allows β-catenin to migrate into the nucleus and initiate downstream pathways, thereby promoting renal fibrosis. (2) After an acute insult, TGF-β1 becomes activated and binds to its receptor, which in turn phosphorylates SMAD2/3. The phosphorylated SMAD2/3, along with SMAD4, then translocates into the nucleus to activate the expression of miRNA-21 and miRNA-192. This activation ultimately leads to renal fibrosis. Concurrently, Smurf1/2 is activated by the SMAD2/3/4 complex, which diminishes the inhibitory capability of SMAD7. (3) The activation of the Hippo pathway leads to the phosphorylation of MST1/2, SAV1, LAST1/2, and MOB1, which contributes to the degradation of YAP/TAZ. Conversely, the inactivation of the Hippo pathway results in the activation of YAP/TAZ, allowing this complex to migrate into the nucleus. This migration initiates cellular proliferation and contributes to the development of renal fibrosis. Abbreviations: FZD, frizzled protein; LATS1/2, large tumor suppressor; LAP, latency-associated peptide; LRP, LDL receptor-associated protein; LTBP, latent TGF-β1 binding protein; MMP-7, matrix metalloproteinase 7; MOB1, MOB kinase activator 1; MST1/2, STE20-like serine/threonine kinase 1/2; P, phosphorylated; SAV1, Salvador 1; Smurf, Smad ubiquitination regulatory factor; TAZ, tafazzin; TCF/LEF, T cell factor/lymphoid enhancer factor transcription factor; TEAD1–4, TEA domain DNA-binding family members; TGF-β1, transforming growth factor-β; TRPC6, transient receptor potential canonical 6; YAP, yes-associated protein.

Figure 3

Binding of angiotensin II to the AT1 receptor activates the RhoGEF/RhoA/ROCK cascade, leading to overexpression of NF-κB, PAI-1, MAPK/ERK 1/2, and NADPH oxidases. NADPH oxidases, as ROS-generating enzymes, increase oxidative stress, thereby upregulating the TGF-β/SMAD and MAPK/ERK pathways. This cascade results in organ remodeling and tissue fibrosis. Additionally, AT1R activation alters intracellular NO and calcium levels via the PI3K/Akt pathway and disrupts the autoregulation of the kidney through arteriole vasocontraction. A downward arrow indicates a decrease in the substance level, while an upward arrow signifies an increase. Abbreviations: AT1R, angiotensin II receptor type 1; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa-B; NO, nitric oxide; PAI-1, plasminogen activator inhibitor-1; PI3K/Akt, phosphatidylinositol 3-kinase/protein kinase B; TGF-β, transforming growth factor-β.