Are Increased Levels of Nitric Oxide a Sign of Kidney Damage in Lupus?
- Association of Serum Nitrate and Nitrite Levels With Longitudinal Assessments of Disease Activity and Damage in Systemic Lupus Erythematosus and Lupus Nephritis
- Arthritis & Rheumatism, Volume 58, Number 1, January 2008, pp. 263-272
What is the topic?
Lupus disease activity often occurs without any apparent signs or symptoms. This is especially true when lupus affects the kidneys, which is known as lupus nephritis. It is possible for lupus to cause significant kidney damage even before a patient is diagnosed.
However, though there may be no visible symptoms, there are chemical changes occurring in the cells and tissues that can be measured. Therefore, a major emphasis among lupus researchers is to find simple laboratory tests can be used to detect otherwise silent lupus disease activity. A laboratory test that can be used in this way is called a biomarker. One potential biomarker that is being investigated is nitric oxide (chemical symbol, NO), since NO is one of the chemicals involved in the body’s immune response.
What did the researchers hope to learn?
The researchers wanted to see if there was any relation between the level of NO and lupus, and if increased levels of NO were related to lupus nephritis.
Who was studied?
Eighty-three adult lupus patients and 40 healthy people of similar age and background were recruited for this study. Ninety five percent (95%) of the lupus patients were women; 80% were African American; both percentages were higher than those in the healthy group. The researchers divided the 83 lupus patients into three groups: (1) lupus patients with no history of nephritis; (2) lupus patients with history of nephritis but no active kidney disease; and (3) lupus patients with active kidney disease that required a biopsy (a biopsy involves removing tissue from the kidney and studying it with a microscope and with other special laboratory techniques). Among the 83 lupus patients, 49 either had a history of nephritis or had active nephritis over the course of the study.
How was the study conducted?
At their first visit, all of the patients had blood samples taken, and these blood samples were tested for levels of nitrates and nitrites, which are indications of nitric oxide production; together the nitrates and nitrites are called NOx. The researchers compared the NOx levels of the lupus patients and the controls. They also did further comparisons of the lupus patients’ NOx levels with other standard laboratory measures used to evaluate lupus, such as the presence of certain antibodies and other immune system agents (called complement) in the blood, or protein in the urine. The lupus patients had regularly scheduled visits every 3 months for at least one year (some were seen for as long as two years). During those visits further blood tests were taken to measure NOx levels at that time, and other tests conducted to evaluate their lupus disease. Patients who had signs of active lupus nephritis had biopsies of their kidneys. Since both smoking tobacco and certain foods can raise the blood levels of NOx, participants in the study agreed not to smoke and to eat only a low-NOx diet 24 hours before each visit.
What did the researchers find?
As expected, the researchers found that the blood levels of NOx in the lupus patients were significantly higher than those without lupus at the first visit. Furthermore, among the lupus patients, those with active lupus nephritis had higher levels than in the other groups. Also, higher levels of NOx were associated with several of the standard laboratory measurements for lupus, including elevated levels of protein in blood and urine (which are signs of kidney disease) and lowered complement, especially the C3 form of complement. Over time, higher NOx levels were associated with greater lupus disease activity.
Turning their attention to the group of patients who had undergone a biopsy for active lupus nephritis, the researchers found that the patients with the highest level of NOx also had the most serious degree of kidney damage. They also looked at how the patients with kidney disease responded to medical treatment; those patients who did not get better (“non-responders”) had higher levels of NOx than those who did respond.
There are two reasons why a chemical can be increased in the bloodstream: either the body is making increased amounts, or the body is not efficiently eliminating the chemical which is being made. The researchers did another series of tests to make sure that the NOx levels were a result of higher production and not because the kidneys were less able to remove the NOx compounds from the blood. Those tests showed that it was, indeed, increased production and this appeared to be related to the activity of C3 complement.
All of these findings led the researchers to conclude that elevated levels of NOx in the blood could be a potential useful marker for lupus disease activity. They also suggested that any medication that aimed to prevent kidney damage in lupus patients might have to limit the production of NO. However, just because something is a marker for disease activity does not necessarily mean that all effective treatments would have to eliminate it. If NO is triggering something else that damages the kidney, then a treatment aimed at that second thing might be effective for nephritis regardless of the NO level.
What were the limitations of the study?
The size of the study group -- 83 lupus patients -- was small, especially considering how different the inflammation of lupus can be from one person to the next. Also, nearly 80% of the lupus patients in the study were African Americans; that is a good aspect of the study, since people of African descent may have worse kidney involvement and have previously not been studied well enough. However this does limit the ability to draw conclusions about people with lupus who might be from different genetic backgrounds.
There are also some limitations to the measurements used. As the researchers themselves pointed out, lupus activity rises and falls over time, and measurements taken at three-month intervals really may not capture important information during the intervening months. Of less concern, but something that should be noted, the researchers didn’t really measure the levels of NO itself, but used the blood levels of nitrate plus nitrite as indicators of NO production. This measurement seems to be useful, but much more could be learned about the specific chemical changes that are going on and in what way they may impact the kidney.
What do the results mean for you?
A number of previous studies had pointed to increased NO production as an important factor in lupus, but those studies were "after the fact"; they only looked back at the records of lupus patients to see if there were any associations. This was the first study to examine the relationship going forward, following lupus patients over time, and gathering information about NO levels in the course of their treatment and evaluation. Thus, it adds strength to the notion that NO may be a useful biomarker for lupus disease activity that could help doctors know what is going on when their patients may not have obvious symptoms. Their suggestion that limiting NO production might be important to consider for new medications for lupus nephritis is also very intriguing. Both of these points -- the value of NOx as a biomarker and its role as a target for new medications -- are definitely worthy of further studies.