Acute kidney injury (AKI) is a clinical condition associated with numerous poor prognoses. Early diagnosis and treatment can greatly improve patient prognosis, which is the primary motivation for finding AKI markers. But beyond that, AKI markers can reveal the molecular mechanisms underlying this complex and heterogeneous disease and can be used as molecular phenotyping tools for direct clinical intervention in AKI.
AKI is not a single disease, but a clinical syndrome that is the result of numerous kidney injuries and consists of multiple factors. Therefore, it seems impossible to obtain excellent diagnostic efficacy using a single AKI marker.
Professors Alge and Arthur of the Department of Nephrology at the Medical College of South Carolina have described the mechanisms, marker-mediated therapeutic and prognostic properties of novel AKI markers in the context of current advances in AKI markers, and this review was recently published in the journal CJASN.
Novel AKI markers
1. Neutrophil gelatinase lipid transport protein (NGAL) urine and plasma NGAL can be used to predict the development and progression of AKI.
NGAL is a widely expressed protein in the lipid transport protein family with a size of 25 KD. Intrarenal NAGL levels are significantly increased at the transcriptional and protein levels after ischemic or nephrotoxic injury.
Plasma NGAL concentrations increase after AKI, and NGAL is filtered through the glomerulus and reabsorbed in the proximal tubule. Elevated NGAL can be detected in the urine 3 hours after injury, peaking at 6 hours, and there is evidence that elevated concentrations can persist for up to 5 days after kidney injury.
2. Kidney injury molecule-1 (KIM-1) KIM-1 is a transmembrane protein with a molecular weight of 38,7kD, including extracellular mucin and immunoglobulin domains. It is expressed at low basal levels in normal kidneys and at elevated levels after local ischemia-reperfusion injury.
KIM-1 protein is localized to proliferating differentiated epithelial cells in the proximal tubule 48 hours after AKI injury.
3. Interleukin-18 (IL-18) is a pro-inflammatory cytokine with a molecular weight of 22 kD that is elevated in large amounts after local ischemia-reperfusion injury, glycerol injection, and platinum-mediated renal injury in the kidney.
IL-18 is a highly regarded indicator in biomarker-mediated therapy because of its possible role in the inflammatory process during the developmental phase of AKI.
4. Liver fatty acid binding protein (L-FABP) L-FABP is expressed in the renal cortex, has a molecular weight of 14 kD, is found mainly in the proximal tubule, and has antioxidant properties as a renal protective protein.
Urinary L-FABP is elevated in cardiac surgery patients immediately after surgery, and it may develop into AKI, peaking within 6 hours.
5. Elevated urinary angiotensinogen is associated with progression of AKI and poor prognosis, such as prolonged hospitalization, need for renal replacement therapy (RRT), and death, in AKI patients after cardiac surgery and in AKI patients with non-surgical causes.
6. Tissue inhibitor of metalloproteinases -2 (TIMP-2) TIMP-2 is a novel AKI marker, and several recent studies have demonstrated its role in different clinical stages of AKI, but its role in AKI is more complex.
7. Insulin-like growth factor binding protein 7 (IGFBP7) IGFBP7, a widely distributed protein with a molecular weight of 29 kD, started to be considered as a tumor suppressor and a regulator of cellular senescence. Like TIMP-2, IGFBP7 has only recently been identified as an AKI marker in studies.
Relationship between novel markers and the development of AKI
These novel AKI markers are present at all clinical stages of AKI and reflect molecular and cellular events in the development of AKI.
The changes in the concentration of each marker over time during the development of AKI are shown in Figure 1.
Figure 1. Changes in AKI marker concentrations over time after renal injury
The role of each renal marker in the different stages of AKI and even CKD is shown in Figure 2.
Figure 2. Integrated model of renal markers
This model divides the clinical stages of AKI into four phases: initiation, development, repair and chronic kidney injury, and the detailed development process is as follows
1. in the initiation phase, there is a rapid decrease in GFR.
2. in the developmental phase, GFR continues to decline, AKI progresses from mild to aggressive, and IL-18 peaks in the developmental phase
3. angiotensinogen rises during the developmental phase and contributes to the development of chronic kidney injury.
4. in contrast to IL-18 and angiotensinogen, NGAL and L-FABP are nephroprotective
5. TIMP-2 and IGFBP7, recently identified early markers of AKI, have also been found to be nephroprotective
6. The repair phase includes the reestablishment of normal cellular and physiological function, which begins only 2-3 days after the initial injury and lasts for more than a week. Persistently elevated NGAL and L-FABP may be associated with repair
7. urinary KIM-1 concentration peaks 48 hours after injury and is also a pre-repair marker
8. angiotensinogen has been recognized as a marker of the CKD process, and urinary angiotensinogen is thought to reflect intrarenal RAS activity, a promoter of CKD, and elevated urinary angiotensinogen during AKI may promote the development of CKD.
9. Similarly, KIM-1 and NGAL expression remains elevated after AKI, indicating continued renal injury and a transition to chronic kidney disease.
These novel AKI markers play an important role in the progression from acute to chronic kidney injury, and their combined analysis may offer hope for the early diagnosis and treatment of AKI.