NGAL as early AKI biomarker
NGAL – the modern marker for early detection of acute kidney injury (AKI)
Acute kidney injury (AKI) is characterized by a sudden and continuous loss of renal function. Clinically this condition represents a principally reversible loss of kidney function. At a later time when the kidney has already been seriously damaged, an increase in metabolic products such as urea or creatinine in the blood plasma and a decrease of the renal filtration capacity or urine volume occur.
Once the common global parameters return to normal laboratory values lying within the reference ranges the patient is considered as cured. A temporary damage of the kidney, however, does not remain without consequences. A study of Lo et al. in 556.090 patients shows that an episode of dialysis-requiring AKI is associated with a 28-fold increased risk of a chronic kidney disease stage 4 or 5, and a greater than 2-fold higher risk of death, respectively (Lo LJ et al. Kidney Int, 2009). This is of public interest as healthcare expenses for hospital-acquired AKI in the USA are estimated by the National Center for Health Statistics to exceed 10 billion $ US per year (Chertow GM et al. J Am Soc Nephrol, 2005).
AKI occurs in 5 to 7% of all hospitalized patients and is associated with high morbidity and mortality (Mishra et al. Lancet, 2005; Chertow GM et al. J Am Soc Nephrol, 2005). 50% of all cases of AKI are caused by ischemia, 35% by nephrotoxic influences, and 15% by infection or autoimmune reactions leading to acute glomerulo- or tubulo-interstitial nephritis (Mehta RL et al. J Am Soc Nephrol, 2003).
There exist several triggers for an AKI such as:
Septic, hemorrhagic or cardiogenic shock leading to hypoperfusion / lack of oxygen. Major surgery, e.g. due to aortic clamping shutting off the blood supply to the kidney during cardiopulmonary bypass.
Damage of kidney tissue by poisonous effects from e.g. cancer chemotherapeutic agents, intravenous X-ray contrast dyes, antibiotics (e.g. aminoglycosides), some NSAIDs, toxins, and poisons.
Infections or immune reactions leading to acute glomerulo-or tubulo-interstitial nephritis.
Various ischemic, immunological, inflammatory or infectious insults, and possibly drug-related nephrotoxicity in a few cases. Results include absent or delayed graft function or acute rejection.
A large number of these patients have to undergo hemodialysis. The decision for the onset of this therapie is taken based on several clinical, radiologic and laboratory results. Classical parameters are mainly urea, creatinine, cystatin C. Since the treatment is correlated with the clinical outcome, however, early diagnosis is crucial.
Among the latest biomarkers, NGAL (neutrophil gelatiniase associated lipocalcin) is becoming increasingly established in clinical use. This protease-resistant polypeptide is expressed in the kidney, particularly in renal tubular cells. The NGAL concentration rises just 30 minutes following a renal damage depending on the degree and duration of the underlying damaging effect (e.g. ischemia). Therefore, this biomarker is applicable for the early diagnosis and assessment of the degree of AKI.
Measuring NGAL is especially useful for:
- a risk stratification of patients in A&E departments regarding the decision for ICU admission and the differentiation between prerenal and intrarenal AKI
- an early decision for or against initiation of renal replacement therapy
- the monitoring of ICU patients where up to 50% of all patients may develop AKI. Including NGAL as a simple screening parameter will provide the earliest warning of this serious complication and hence the best opportunity for improving outcome, especially for patients with inadequate source control (in SIRS (severe inflammatory response syndrome) and MOD (multiple organ failure)). NGAL may reduce the duration of stay of patients on the ICU by earlier therapy decisions.
- the detection of kidney injury caused by cardiopulmonary bypass surgery; monitoring NGAL levels reveals kidney injury that may result from the procedure
- the predictive evaluation of graft function and survival after kidney transplantation
- the monitoring of renal function after administration of intravenous iodine contrast agents used in diagnostic imaging
- the evaluation of efficacy and safety of new medical interventional therapies and drugs
* Note: In contrast to the video, which claims that NGAL is released from the distal tubules of the nephron after AKI, early studies from Matthaeus et al. (1) and Mishra et al. (2) demonstrated, that NGAL was principally upregulated in the proximal tubules of the nephron (and in cultured human proximal tubule epithelial cells) after ischemia.
The region of the nephron that releases most NGAL into the urine is thus controversial.
(1) Matthaeus T, Schulze-Lohoff E, Ichimura T, Weber M, Andreucci M, Park KM, Alessandrini A, Bonventre JV (2001) Co-regulation of neutrophil gelatinase-associated lipocalin and matrix metalloproteinase-9 in the postischemic rat kidney. J Am Soc Nephrol 12:787A.
(2) Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, Barasch J, Devarajan P (2003) Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 14:2534-2543.