Leading the way to a cure

Lupus Research Update: 2008 Volume 1

Volume 1, 2008 - Online Edition | In This Issue

ALR Funded International Consortium Identifies Genes Linked to Lupus >
The Faces of Lupus: Eddie Kennison, Kansas City Chiefs >
Meet the Investigator — Mary K. Crow, M.D., Named Chair of Scientific Advisory Board >
Research Results — A New Clue in the Survival of Autoimmune B Cells >
Research Results — Narrowing Down a Lupus-Related Gene >
Research Results — Finding Hidden Clues to Children's Lupus Nephritis >
Research Results — Finding Ways to a Safer Pregnancy for Women with Lupus >
Drug Research and Development News >
Leaving a Legacy >

Research Results — Finding Hidden Clues to Children's Lupus Nephritis

Several researchers funded by the Alliance for Lupus Research are searching not just for biological clues that could lead to new treatments for lupus, but for biochemical hints to help diagnose the disease and its complications earlier and assess how well treatments work—without requiring complicated, painful and/or invasive tests.

One grantee having significant success in that area is Hermine Brunner, M.D., an associate professor of pediatric rheumatology at Cincinnati Children's Hospital Medical Center, and her team. They recently published two articles in the print and online journal Pediatric Nephrology about their work to identify biomarkers for lupus nephritis, or lupus-related kidney disease, in children.

One such marker is called neutrophil gelatinase- associated lipocalin, or NGAL. This protein is produced by several cells in the body, including kidney cells and cells involved in inflammation, called granulocytes. NGAL appears to be associated with kidney damage or injury, with levels changing based on the degree of renal disease activity.

"When we looked at NGAL in the urine of patients with lupus nephritis we found they had very, very high levels," Dr. Brunner said. However, blood levels of NGAL in the same patients weren't nearly as high, she said. The meaning? "NGAL is a very sensitive marker with a very high accuracy for identifying patients with active renal disease."

You might think doctors would already know which of their patients have active kidney disease. But the disease can exist for months or longer without any clinical signs, even as the kidneys undergo significant damage. The primary sign—protein in the urine—could be due to numerous causes, Dr. Brunner explained, including an infection. Plus, certain medications that reduce the amount of protein the kidneys release, effectively "masking" active renal disease.

The only sure way to know if a patient has lupus nephritis, she said, is with a biopsy, an invasive procedure in which a small bit of the kidney is cut out and examined under a microscope. And that, as you can imagine, is not something children want to undergo very often.

But as Dr. Brunner's work showed, measuring urine levels of NGAL provides a simple way to determine not only the existence of the disease, but its severity. That's because the worse the disease, the higher the levels of NGAL. Plus, commonly used medications in children with lupus don't seem to affect NGAL levels.

Even better is the preliminary finding that NGAL may serve as a predictive marker weeks before kidney damage begins, enabling an earlier start to treatment to slow or prevent that damage.

In their other paper, Dr. Brunner and her group reported the identification of a "proteomic signature" in the urine of children with lupus nephritis. The team used new screening techniques to evaluate hundreds of potential proteins in children's urine for any connection to lupus nephritis; they found four that appear especially suitable for identifying active lupus nephritis.

"We could see that even children with lupus without overt nephritis had different proteins in their urine compared to [the control sample]," she said. They also found that the biomarkers are very specific for renal disease in people with lupus, but not for other lupusrelated disease activity.

"That's important because we want specific information on renal nephritis because controlling renal nephritis is critical for the long-term prognosis of the patient and among the major determinants of long-term survival," Dr. Brunner explained.

Because the proteins are the end products of abnormal cellular function, identifying the chemical pathways that lead to them could result in new targets for treatment, she said.

Together with the NGAL link, Dr. Brunner said, these findings represent the first step in the creation of a "lupus renal panel," a noninvasive urine test that could be routinely performed to monitor kidney health in people with lupus, providing a major step forward in managing one of the most devastating affects of the disease.

Brunner HI, Mueller M, Rutherford C, Passo MH, Witte D, Grom A, Mishra J, Devarajan P. Urinary neutrophil gelatinase-associated lipocalin as a biomarker of nephritis in childhood-onset systemic lupus erythematosus. Arthritis Rheum. 2006 Aug;54(8):2577-84. Suzuki M, Ross GF, Wiers K, Nelson S, Bennett M, Passo MH, Devarajan P, Brunner HI. Identification of a urinary proteomic signature for lupus nephritis in children. Pediatr Nephrol. 2007 Dec;22(12):2047-2057. Suzuki M, Wiers KM, Klein-Gitelman M, Haines KA, Olson J, Onel KB, O'Neil K, Passo MH, Singer NG, Tucker L, Ying J, Devarajan P, and Brunner HI. Neutrophil Gelatinase Associated Lipocalin as A Biomarker Of Disease Activity In Pediatric Lupus Nephritis. Pediatric Nephrology. Published online January 2008.

Just the Facts

What the study showed:
Biomarkers in the urine of children with lupus appear to be correlated with lupus nephritis and, based on current research, are more accurate for diagnosing active lupus nephritis than current laboratory tests. What it means: These biomarkers could provide early warning signs of lupus nephritis before severe damage occurs and quickly identify which treatments work. If proven effective, a less invasive testing method could be brought to market for faster and easier diagnosis of this complication from lupus.

What's next:
Further validating the findings and assessing how they respond to various therapies.

ALR funding:

1.5 million

people in the U.S. have Lupus.

172 million

dollars committed to lupus research by the Lupus Research Alliance.

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