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BIOMARKERS OF ACUTE NEPHROTOXICITY

N.A. Buckley
1,2

1
South Asian Clinical Toxicology Research Collaboration, www.sactrc.org.
2
University of NSW, Sydney, Australia. Email: n.buckley@unsw.edu.au

Abstract
There are number of clinical toxicological situations where acute renal injury is very common
and apparent with current tests (e.g. paraquat, MCPA, glyphosate, Cleistanthus collinus,
Gloriosa superba poisonings, & Russell’s viper envenomation) and a number where it is less
apparent but we have good reason to suspect sub-clinical toxicity is also common (e.g.
paracetamol & aspirin poisoning). The range of mechanisms of renal toxicity of these
substances covers a diverse range of pathophysiological mechanisms (e.g. oxidative stress,
inhibition of specific transporters, haemoglobinuria, myoglobinuria, inflammatory, vascular) and
all major functional regions of the kidney (vasculature, glomerulus, proximal and distal tubules,
collecting ducts).
Current biomarkers for renal injury (creatinine, BUN and urinalysis) are insensitive, delayed and
non-specific, particularly as they are usually applied in practice. More considered use of non-
steady-state calculations of creatinine clearance might greatly improve the speed and accuracy
of the diagnosis of acute kidney injury. However, these traditional renal biomarkers provide no
insights whatsoever in to the mechanism, site or stage of renal toxicity.
There are many new biomarkers that directly measure kidney injury, the response to injury or
specific functions and some are also specific to parts of the nephron. Such biomarkers include
urinary KIM-1, beta2-Microglobulin, Cystatin C, Clusterin, Trefoil factor-3, NAG, NGAL and IL-
18. All have received significant support as being potentially superior biomarkers for detecting
nephrotoxicity in animals and for rapid detection of other causes of kidney injury in humans.
However, there is currently very little research assessing long term renal outcomes of acute
toxic renal injury in humans using these biomarkers. Thus, the prognostic significance of ‘acute
kidney injury’ as detected by these new novel biomarkers is entirely unknown.
Better biomarkers are worth pursuing further as diagnostic tests in clinical medicine, as early
markers of nephrotoxicity in drug-development, or in research to reduce acute kidney injury. In
particular this may lead to phase-specific biomarkers that might support phase-specific
interventions. It might also identify biomarkers from an acute injury that are associated with
long-term renal damage.
The problems of toxic acute kidney injury, snakebite and serious poisoning are all far more
significant in Asia than in Western countries, and this region should take a lead in research in
this field. A better understanding of the pathophysiology of these conditions and tools to
measure them may lead to better treatments. Demonstrating the relevance of human renal
toxicity biomarkers would also improve clinical research on chronic renal disease, another major
health problem of this region. For example, it might lead to diagnostic criteria for nephrotoxicity
in patients with idiopathic renal disease. Markers that reliably detect acute toxic effects very
early in the progression of this disease would allow links to be made with possible causes.
However, the time course and magnitude of elevation of these biomarkers after acute toxic
injury are needed to interpret exposure data. The best source of such data can be provided by
clinical toxicologists in Asia.