Existing Drugs Show Promise For Treating End-stage Renal Disease In Lupus

Mishra, a rheumatologist at Wake Forest University Baptist Medical Center, had previously reported that an anti-seizure medication and a chemotherapy drug were effective at preventing skin and kidney disease in mice with lupus. In the current research, he explored why the drugs were effective -- with the goal of understanding more about what goes wrong to cause the disease.

In one project, Mishra studied the success of the anti-seizure medication valproic acid (Depakote®) in preventing kidney and skin disease in mice with lupus. Lupus is an autoimmune disorder, which means that the immune system attacks tissue and organs including the joints, kidneys, heart, lungs, brain and blood.

About half of patients with lupus have kidney disease. Fibrosis, or thickening of the kidney, is one of the most common reasons that patients require dialysis. The development of skin lesions is another common symptom.

Mishra's theory was that valproic acid helps reduce activation of B cells, which are white blood cells involved in the body's immune response, including in the production of antibodies in lupus patients. Various research teams are studying how to deplete B cells or decrease their activation.

"This is a different approach using a common drug to prevent B cell activation in lupus," he said.

The study was designed to determine if valproic acid reduces B cell activity by targeting histone deacetylases, which reduce the expression of genes. Mishra was the first to establish an association between abnormal histone codes and the causes of lupus. Velproic acid is known to target a specific histone deacetylase (number 2 or HDAC2).

The researchers found increased expression of HDAC2 when B cells were activated in mice with lupus, compared with normal laboratory mice. They then treated half of a group of mice with lupus with valproic acid, and half received a placebo, or inactive treatment. No mice in the valproic acid treatment group developed skin disease, whereas all mice in the placebo group did. In addition, 90 percent of treated mice had low levels of protein in the urine (high levels are a sign of kidney disease), compared to 20 percent of the non-treated group.

"These data suggest that specific inhibitors of HDAC2, such as depakote, can decrease antibody production and prevent skin and kidney disease in lupus," said Mishra. "Our goal is to test the medication in patients with the disease."

A separate project involved the drug mithramycin, which is used to treat cancer and decrease calcium levels in the blood. The researchers theorize that the drug targets a specific transcription factor, Sp1, which is a protein that controls several genes, including one that causes end-stage renal disease and kidney fibrosis. They believe that reducing the activity of these genes may have a beneficial effect on patients with lupus.

"This is a fairly new approach -- using a transcription factor to target kidney disease in lupus patients," said Mishra.

They tested the drug in mice with lupus -- half got the drug and half got a placebo. At the end of the eight-week study, 90 percent of the mice in the non-treatment group had renal vasculitis, inflammation of the tiny blood vessels in the kidney that can lead to kidney failure, compared to 30 percent in the treatment group. In addition, 60 percent in the non-treatment group had high levels of protein in the urine (a sign of kidney disease), compared to 22 percent in the treatment group. In addition, kidneys in the treatment group showed significantly decreased expression of the genes controlled by Sp1.

"Targeting Sp1 with mithramycin or other drugs that can inhibit this molecule should benefit lupus patients," said Mishra, who added that the group hopes to test the treatment in patients with lupus. He said the drug could potentially help prevent kidney disease as well as treat it.

Co-researchers were Isaac Snowhite, Ph.D., Sabiha Shahnaz, Ph.D., Anh Nghiem, B.S., and Phil Ruiz, Ph.D., all with Wake Forest.