MELBOURNE (FRONTLINE MEDICAL NEWS) – Researchers have identified six microRNAs that may indicate a better likelihood of response to cyclophosphamide in patients with lupus nephritis, according to a study presented at an international conference on systemic lupus erythematosus.

“MicroRNA has been shown to be important in systemic lupus in several studies, and they’ve identified several microRNA that have been shown to affect the outcome measures in patients,” said Sarfaraz Hasni, MD, director of the Lupus Clinical Research Program at the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Md., who presented a poster on the study at the meeting.

Dr. Hasni said that microRNA, which are small, noncoding RNA that play a role in the regulation of gene expression, have also been shown to have altered expression levels in a variety of diseases.

The aim of this study, involving 71 patients with lupus nephritis, was to look for microRNAs associated with treatment response to cyclophosphamide.

The first stage of the study involved isolating microRNAs from kidney biopsies taken from a first cohort of 17 responders and 15 nonresponders.

Responders were patients who, after 2 years of intravenous cyclophosphamide, showed no active urinary sediments, less than five red blood cells or white blood cells in urine, and proteinuria below 1 g/24 hours.

After analyzing 300-400 microRNAs in these biopsies, the investigators identified 6 that were significantly upregulated in association with treatment outcome in both the first cohort as well as a second validation cohort of 22 responders and 17 nonresponders.

When the researchers looked at the most likely genetic targets of these microRNAs, they identified genes associated with G2/M DNA damage checkpoint regulation, which points to a link with cyclophosphamide efficacy, as well as associations with immunological disease and renal inflammation.

Dr. Hasni said that previous studies of microRNA had looked in the peripheral blood but suggested this may not necessarily reflect what was happening in the kidney.

The next step for researchers is to see if upregulation of these microRNAs is predictive of treatment response.

“If you are giving cyclophosphamide for 2 years, it comes with a high risk of side effects, especially in young women because there is potential for premature ovarian failure,” Dr. Hasni said in an interview. “If we can predict that this patient is not going to respond to cyclophosphamide or will not have a good outcome, we can use alternative therapy, or perhaps use more aggressive or a combination therapy approach rather than keep doing the same thing and 2 years later find out the patient is not going to respond.”

The researchers are also keen to investigate whether these same microRNAs can be isolated from serum or urine, which would reduce the need for kidney biopsy.

“The testing for microRNA is not that hard – it’s the biopsy and extracting the tissue from the biopsy… that’s obviously cumbersome and can only be done in a research setting.”

No conflicts of interest were declared.


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