Boston, MA, June 21, 2010 --(PR.com
)-- The kidney is one of the primary targets for toxicity of drugs. Two serum biomarkers, serum creatinine (SCr) and blood urea nitrogen (BUN), are commonly used to detect kidney toxicity in preclinical and clinical studies and in routine clinical care. Both, however, have severe limitations relating to sensitivity and specificity.
New research from the laboratories of Vishal S. Vaidya, a Fellow in the Renal Division at Brigham and Women’s Hospital (BWH) and Assistant Professor of Medicine at HMS and Joseph V. Bonventre, the Samuel A. Levine Professor of Medicine, Health Sciences and Technology at HMS and chief of the renal division at BWH in collaboration with the Predictive Safety Testing Consortium, has resulted in the approval of Kidney Injury Molecule-1 (Kim-1) as a highly sensitive and specific marker of drug-induced kidney injury by both the FDA and EMA and is expected to greatly facilitate evaluation of tubular toxicity in certain preclinical and clinical settings.
The study, published in the May issue of Nature Biotechnology, used eleven mechanistically distinct models of kidney injury to compare the diagnostic performance of urinary Kim-1 to BUN, SCr and urinary N-acetyl-b-D-glucosaminidase (NAG) as predictors of kidney tubular damage scored by histopathology. The researchers found that whether the kidney injury was induced by well-established kidney toxicants or ischemia, urinary Kim-1 outperformed BUN, SCr and urinary NAG, which are conventional markers for assessing renal injury.
In the current study Vaidya, Bonventre and collegues show that the sensitivity of Kim-1 was nearly perfect, irrespective of the mechanism of kidney injury and remained high whether the entire histopathology grade of low to high was included or whether the analyzed group was restricted to low histopathology grade. This study clearly demonstrates that current markers of assessing nephrotoxicity, BUN and SCr are effective only with more severe injury in preclinical studies. For example, the sensitivity of SCr was remarkably low at 0.20 (where 0 is low and 1 is perfect) for subtle damage to the kidney at histology grade 1 (where 1 is low and 3 is high) and increased to only 0.56 with severity grades of 3. In contrast, urinary Kim-1 was sensitive and specific for assessing subtle forms of proximal tubular damage with the sensitivity greater than 0.88 whether the histology grade was 1 or 3.
Qualification of KIM-1 as a biomarker for clinical applications will involve a systematic evaluation of the diagnostic performance of KIM-1 in well-controlled observational and/or interventional clinical protocols using both standard-of-care agents with known nephrotoxic properties and/or exploratory agents with renal safety concerns. The opportunity to use the same translational marker such as Kim-1 for both the preclinical and clinical setting facilitates clinical monitoring of toxicity that has been demonstrated at higher doses in preclinical development or in a single test species when human relevance is suspected.
It is in the interest of the pharmaceutical industry, health authorities, and patients to prevent new kidney toxic drugs from entering the market and to be able to identify early and best manage nephrotoxicity. The most efficient way to accomplish this is to have sensitive and specific biomarkers of kidney toxicity that can be used in animals early in drug development well before clinical studies are underway.
The Predictive Safety Testing Consortium was established as a collaboration of the pharmaceutical industry, the FDA, EMEA and academia to facilitate the qualification of biomarkers for safety in drug development. It brings together expertise from a variety of disciplines to organize and create evidentiary datasets to present to the regulatory agencies for qualification decision-making.
As a result of the efforts the regulatory agencies will allow drug companies to submit the results generated using Kim-1 and/or six other qualified urinary markers to evaluate kidney damage during animal studies of new drugs. As both regulatory agencies have hitherto required pharmaceutical companies to submit the results of renal toxicity tests separately, this marks the initial use of a framework allowing submission of a single application to both the FDA and EMEA. Both agencies now formally recognize that BUN and creatinine can only detect kidney damage with a significant time delay after it has begun to occur and that urinary biomarkers can both detect cellular damage within hours and identify which nephron segments have been affected. This recognition is a testament to the potential of the biomarkers to provide important advantages relative to the traditional tests.