Acute Kidney Injury (AKI) is a rapid loss of kidney function and is an important event to watch for in preclinical and clinical trials of new drugs. The kidney is a primary target of drug-induced toxicity and even current drugs approved by various regulatory agencies can cause AKI if given improperly or in the wrong combination.
The Critical Path Institute’s Predictive Safety Testing Consortium (PSTC) has proposed the following seven biomarkers associated with nephrotoxicity. Each of the following markers identifies injury to specific regions of the kidney.
- Beta2-microglobulin(B2M) – Beta2-microglobulin normally is filtered out of the blood by the kidney’s glomeruli. When AKI occurs the levels of B2M rise above normal levels.
- Clusterin – A multifunctional glycoprotein with roles in metabolism and transport of lipids. Tissue injury prompts higher than normal expression levels of this protein.
- Cystatin-C (CysC) – Produced in all nucleated cells, this protein is a marker of kidney injury from drug toxicity and many chronic diseases. It is an estimator of glomerular filtration rate and also indicates proximal tubule injury.
- Kidney injury molecule-1 (KIM-1) – An extracellular protein anchored in the membrane of proximal tubule cells. Injury causes increased levels of KIM-1 in urine.
- Albumin – A common class of proteins and there should be minimal levels present in urine. As the kidney fails to filter the blood properly, the levels increase in lab animal or patient samples.
- Urinary Total Protein (uTP) – Total protein should be minimal in urine and upon injury proteins are not properly filtered by the glomerulus.
- Trefoil Factor 3 (TFF3) – A small peptide hormone. Excretion of this molecule is reduced during AKI.
Most of the changes in these markers are temporary with drug-induced AKI and return to normal levels after the drug treatment is halted.