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CATIE News - Emerging candidate biomarkers for monitoring kidney health

15 June 2010 - A widely used assessment of kidney function is the level of the waste product creatinine in the blood. This can be used by itself (as the absolute concentration of creatinine) or it can be used in equations to derive the eGFR (estimated glomerular filtration function). However, kidney and toxicity specialists have known that there are problems when relying on creatinine levels to reveal information about kidney damage. Before we delve into this issue, we first present some information about the workings of the kidneys, which is relevant to the issue of kidney injury arising from exposure to some medicines.

Inside the kidney

The kidneys are complex organs each containing a million tiny filtering units called nephrons. Each day a pair of healthy kidneys filters about 150 litres of blood. The filtered fluid (called the filtrate) is then processed by the kidneys so that several processes happen, including:

  • the acidity of the filtrate is adjusted so that when reabsorption occurs the acid-base balance of the blood is carefully maintained
  • levels of minerals in the blood-sodium, potassium, calcium, magnesium, phosphorus and so on-are carefully regulated so that the appropriate proportions of minerals are reabsorbed from the filtrate into the blood.

Waste products are removed and important substances are reabsorbed into the blood. The kidneys also produce hormones to help maintain the health of the cardiovascular system, muscles and bones and to monitor oxygen levels in the blood. For example, should oxygen levels fall below a threshold, the kidney releases hormones to stimulate the bone marrow to produce more oxygen-carrying red blood cells.

Kidneys can be susceptible to drug toxicity because of their layout and function. As the filtrate moves along the kidneys' complex network of tubes and pipes (called tubules) in each nephron, levels of substances in the filtrate, particularly drugs, rise. Initially this increased concentration of drugs is about three times greater than found in the blood. But as the filtrate moves away from the nephron to more distant parts of the tubules, the concentration of drugs can soar to more than 100 times greater than in the blood. Furthermore, drugs that are processed by the kidneys can produce toxic substances as they are broken down that can injure kidney cells. And the dense network of blood vessels within the kidneys is such that it may enhance the accumulation of toxic substances within these organs.

Researchers are focusing on finding a selection of proteins and other substances produced by the kidney (called biomarkers) that can help identify injured parts of these organs.

Biomarkers today

Two common biomarkers currently used to assess kidney damage are creatinine levels in the blood and blood urea nitrogen (BUN). However, researchers know that these biomarkers have limitations.

Creatinine

Creatinine, a waste product produced from the breakdown of muscle, is filtered by the kidneys. Creatinine levels in the blood can rise when the kidneys are damaged. However, changes in creatinine levels may be insensitive to moderate levels of kidney injury. In some studies with kidney-toxic drugs, substantial injury first needs to occur before it is reflected by changes in creatinine levels. Furthermore, in severely ill patients who do not have a lot of muscle tissue, a great deal of kidney damage has to occur before creatinine levels rise to a high threshold. So, reliance on creatinine may not only underestimate the degree of kidney damage, it may also provide a delayed warning signal.

BUN

Blood urea nitrogen is also widely used to assess kidney health. However, BUN may not be an ideal biomarker for assessing kidney injury because many factors can affect BUN. Even though urea is filtered by the kidneys, it is reabsorbed. BUN levels can also rise when urea production increases; this can occur when protein supplements are used or the body is breaking down its tissues.

Working together

To meet the urgent need for more sensitive biomarkers for kidney health, a large group of scientists, public and private corporations, and research and drug regulatory agencies have formed the Predictive Safety Testing Consortium (PSTC). Key members of the PSTC include the following regulatory agencies:

  • EMA (European Medicines Agency)
  • FDA (Food and Drug Administration)
  • Japanese Pharmaceuticals and Medical Devices Agency

Key biotech and pharmaceutical members of the PSTC include the following:

  • Abbott Laboratories
  • Amgen
  • Bristol-Myers Squibb
  • Boehringer Ingelheim
  • GlaxoSmithKline
  • Hoffmann-La Roche
  • Johnson & Johnson
  • Merck Research Laboratories
  • Novartis
  • Pfizer
  • Sanofi-Aventis

Candidate biomarkers

The consortium reviewed existing kidney toxicity data and commissioned extensive experiments on several thousand rats. As a result, the following biomarkers, which can be found in urine, have been selected for further testing:

  • clusterin (CLU)
  • kidney injury molecule-1 (KIM-1)
  • albumin
  • total protein
  • beta 2 -microglobulin
  • cystatin-C
  • trefoil factor 3 (TFF3)

Emerging from the lab to the clinic

Regulatory agencies have concluded that there is not yet enough information to endorse the general use of these candidate biomarkers in the everyday monitoring of people. However, in an effort to reach this goal, the PSTC plans to conduct clinical trials of six to 12 months in different populations, specifically assessing the impact of factors such as age and gender on the candidate biomarkers. The PSTC will test these biomarkers in people with poor underlying health who have active kidney injury. The biomarkers will also be useful in the area of drug development.

In the public interest

In general, the public perceives that the pharmaceutical industry has a fierce sense of competition and secrecy and, as a result, some citizens distrust the motives of this industry. So the collaboration that is elaborated by the PSTC is overseen by a non-profit American agency called the Critical Path Institute (C-Path). This institute does not accept funding for its operations from any corporation that develops drugs, devices or other products regulated by the FDA. Core funding for C-Path is provided by public or government agencies, private citizens and foundations. As part of its commitment to help maintain public trust, C-Path has a commitment to transparency and will make all results from its consortia public.

The PSTC's nephrotoxicity working group was the first to submit biomarker data to the FDA and EMA for qualification and the seven candidate biomarkers previously mentioned can now be discussed on a case-by-case basis with the FDA and EMA when companies submit studies to assess these biomarkers in people. Regulatory authorities in Japan are reviewing data on the seven biomarkers.

Beyond the kidneys

The collaboration that has been incited by C-Path has not been restricted to kidney safety. The PSTC has also been busy reviewing data on biomarkers for liver and muscle toxicity, so advances in these and likely other areas can be expected in the future.

Acknowledgement

We thank Dr. Joseph Bonventre, Brigham and Women's Hospital , Harvard University, for his for expert review, discussion and research assistance.

-Sean R. Hosein

 

 

 

REFERENCES:

•  Bonventre JV, Vaidya VS, Schmouder R, et al. Next-generation biomarkers for detecting kidney toxicity. Nature Biotechnology . 2010 May;28(5):436-40.

•  Vaidya VS, Ozer JS, Dieterle F, et al. Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies. Nature Biotechnology . 2010 May;28(5):478-85.

•  Ozer JS, Dieterle F, Troth S, et al. A panel of urinary biomarkers to monitor reversibility of renal injury and a serum marker with improved potential to assess renal function. Nature Biotechnology . 2010 May;28(5):486-94.

•  Dieterle F, Perentes E, Cordier A, et al. Urinary clusterin, cystatin C, beta 2 -microglobulin and total protein as markers to detect drug-induced kidney injury. Nature Biotechnology . 2010 May;28(5):463-9.

•  Dieterle F, Sistare F, Goodsaid F, et al. Renal biomarker qualification submission: a dialog between the FDA-EMEA and Predictive Safety Testing Consortium. Nature Biotechnology . 2010 May;28(5):455-62.

•  Woosley RL, Myers RT, Goodsaid F. The Critical Path Institute's approach to precompetitive sharing and advancing regulatory science. Clinical Pharmacology and Therapeutics . 2010 May;87(5):530-3.

 

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CATIE-News is written by Sean Hosein, with the collaboration of other members of the Canadian AIDS Treatment Information Exchange, in Toronto.

From Canadian AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca

Source: CATIE: CANADIAN AIDS TREATMENT INFORMATION EXCHANGE


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