Assessment of kidney function and disease progression have mainly focused on the evaluation of 2 biological standards: the glomerular filtration rate (GFR) and serum creatinine levels.
As kidney diseases are complex and heterogeneous, these parameters omit to evaluate the kidney tubular health and allow a late detection of disease progression only. Therefore, restraining the investigation of kidney disease on these 2 parameters limit the development and evaluation of therapeutic strategies to minimize kidney injury at the early stages of the disease course.
These last years, several new biomarkers have been described with a potential to better determine the clinical health of the different nephron segments and applied from acute to chronic kidney diseases. On the scheme below, we listed some renal specific parameters that we assess in routine in our different experimental systems.
Glomerular Filtration Rate (GFR)
It is calculated by measuring any chemical that has a stable level in the blood and is freely filtered but neither reabsorbed nor secreted by the kidneys. Clinically, blood levels measurement of inulin after injection is still considered as the gold standard for the estimation of GFR. In case of chronic kidney disease or reduction of renal mass, the GFR is reduced that is paralleled with the organ loss of function.
- Human = 0.15-2 mL/min per 100g of BW
- Rat = 0.8-1 mL/min per 100g of BW
- Mouse = 0.8mL/min per 100 of BW
Below a typical 4 stages evolution of GFR in diabetic patients with no therapeutic interventions.
The evaluation of GFR in preclinical experimental models can be performed via the MediBeacon® Patches Technology. This procedure is based on intravenous injection of a fluorescent tracer allowing the evaluation of its blood levels across the animal skin. This strategy avoids the repetitive blood sampling and animal restraining during the monitoring.
Creatinine
Creatinine is a waste product left over from energy-producing processes in muscles. Kidneys filter creatinine from the blood to the urine. In case of kidneys damage, creatinine accumulates in the blood and less is released in urine. The ratio between blood and urine creatinine levels is an effective parameter to detect signs of kidney disease.
- Human = 0.6 to 1.3 mg/dL
- Rat = 0.4–0.8 mg/dL
- Mouse = 0.08-0.12 mg/dL
However, the evaluation of kidney function via creatinine levels only shows several limitations as this biomarker is influenced by multiple factors extrinsic to the kidney (ie, age, sex, muscle mass, metabolism, diet, medications, hydration status…). Furthermore, levels of creatinine do not rise until nearly 50% of kidney function is damaged, leading to inaccurate chronic kidney disease staging and false negatives.
Kidney Injury Molecule -1 (KIM-1)
KIM-1 is a 38.7-kDa glycoprotein expressed at low levels in the kidney and other organs, but it is significantly upregulated when the kidney undergoes injury or nephrotoxicity. In humans, proximal tubule cells are the main sites of KIM-1 expression after injury. This protein is involved in both kidney injury and the associated recovery processes.
Many studies have proposed urinary levels of KIM-1 as a sensitive and specific marker of kidney disease and particularly in acute injuries. Clinically, additional research and trials are ongoing to support the use of KIM-1 in the early diagnosis of AKI.
- Human = <1 ng/mL (increases to 7 ng/mL after IRI)
- Rat = <1 ng/mL (increases to 15 ng/mL after nephrotoxicity)
- Mouse = <1 ng/mL (increases to 7 ng/mL after IRI)
Blood Urea Nitrogen (BUN)
Blood Urea Nitrogen (BUN) is a serum waste product of protein metabolism. This product is filtered by the kidneys and removed from the body in urine. Elevations in BUN levels in the blood are often, but not always, a result of a decrease in GFR. Some factors enhance urea production, such as gastrointestinal bleeding, corticosteroid therapy, or high-protein diet, and limit the utility of BUN in assessing kidney function in these specific conditions.
- Human = 6 to 24 mg/dL
- Rat = 15 to 25 mg/dL
- Mouse = 25 to 45 mg/dL
Neutrophil Gelatinase-Associated Lipocalin (NGAL)
NGAL is a 25 kDa glycoprotein expressed and secreted by proximal and distal renal tubular cells. The NGAL biomarker has been considered as the most promising biomarker of acute kidney injury (AKI) as it rises rapidly (within 2 hours) in response to kidney injury.
This protein plays important roles in nephron recovery during infection, inflammation, due to nephrotoxic drugs. Serum and urinary NGAL have similar sensitivity for assessing renal damage. However, the overall pathologic conditions, like inflammation, sepsis or cancer also upregulate NGAL levels, which may blur the accuracy of NGAL as renal damage indicator.
Normal urinary range:
- Human = 50 ng/mL
- Rat = 20 ng/mL
- Mouse = 30 ng/mL