Personal Story on Lupus & Kidneys

[Carolyn, Director]

Kidney Disease & Lupus by Jenny Thorn Allan
No one forgets the day they were diagnosed with lupus nephritis. For some people, it's the same day they learned they had lupus. For others, the two diagnoses can be years apart.
Both happened to me on the same day. I was 35 and living in California with my husband of just seven months. I distinctly remember going birding on New Year's Day 1993; the next day I had swelling in both legs, from my feet to my knees. I thought maybe a spider had bitten me out in the field.
A few days later, a rheumatologist at Kaiser Permanente told me, "You have systemic lupus erythematosus." I remember thinking that I'd never be able to pronounce those words, much less understand what was happening to me. The doctor went on to say that I also had glomerulonephritis. Hearing that unwieldy string of syllables is when I realized something really bad was going on. A month later, a kidney biopsy confirmed that I had membranous nephropathy, Class IV in the World Health Organization’s six classes of lupus nephritis.
Skip Pruitt, of Falls Church, Va., was diagnosed with lupus nephritis in 1984, a year after his first symptoms of lupus. "I remember it like it was yesterday," he says.
"In 1983, I was 24, attending college in Arkansas. I was very active; I was in the marching band, very physically fit," he says. "I developed excruciating pain in my joints, took antibiotics, and things went back to normal. Then in the springtime in 1984, I developed similar symptoms and gained a lot of weight -- 30 or 40 pounds. At first I thought it was muscle mass because I was working out and lifting weights, but I started feeling sick, and then I noticed pitting in the skin on my legs. It turns out that was from the water retention."
Pruitt was going to wait to get checked out by a doctor, until his parents flew in from Michigan, but instead he was admitted to the emergency room the night before they arrived. "My creatinine level was high, my potassium level was very high, and my kidney function was low," he recalls.
Pruitt didn't have another lupus flare until 1994. "That's when I finally had a kidney biopsy as part of joining an NIH protocol for a clinical trial on a low dose of a chemotherapy drug, cladribine (Leustatin®). There was irreparable scarring found in my kidneys. The biopsy showed Class IV nephritis," he says.
Mary Francolic, of New York City, was 31 when she was diagnosed with lupus in 1996. "It was mostly joint pain and a slight fever, but the pain wasn't severe," she says. She, too, was given antibiotics because her doctor thought it was the flu. But when the antibiotics didn't work, and she developed aching all over her body and more fever, she underwent more testing.
"My doctor thought it could be lupus and referred me to a rheumatologist in my area, and after more testing she confirmed that it was lupus," Francolic says. "There was no kidney involvement, though."
Her kidneys weren't affected until nine years later.
"By then it was June of 2005. The summer (in New York City) had just started," she remembers. "My parents said maybe my ankles were so swollen because of the heat. When I went to the doctor, I had high blood pressure. A urine test showed that protein was leaking from my kidneys into my urine."
Francolic's rheumatologist told her to see a nephrologist, but it took Francolic several months to find someone. "Most of the nephrologists in the area weren't taking new patients," she says, "so I waited two months for an appointment, then another month after the tests were done. I finally had a kidney biopsy, which confirmed Class IV lupus nephritis."
The Reality of Lupus Nephritis
These stories describe three cases of lupus, all with very different time frames for the development of nephritis. It's estimated that up to 40 percent of individuals with lupus develop kidney disease.
Healthy kidneys maintain the delicate balance of substances necessary to a body’s normal function, such as electrolytes (sodium, potassium, chloride), minerals (calcium, magnesium, phosphorus), and other compounds (glucose, protein). They do this by reabsorbing what the body needs and filtering out the rest.
Every day, kidneys filter about 100 -150 quarts of blood to excrete out about one to three quarts of waste products and extra water, and pass it out through the urine. The filtering occurs in tiny units inside your kidneys called nephrons (neh-FRONZ).
Most kidney diseases affect the nephrons, causing them to lose their filtering capacity, and in most situations both kidneys are affected. Inflammation of the nephrons is called nephritis. Kidney diseases destroy the nephrons. This may occur slowly and silently, with the damage becoming apparent only after years or even decades. In some cases, however, the damage happens quickly, and over days to months there is a complete loss of function.
Damage also may be caused to the cells and basement membranes within the glomerulus that filters the blood into the urine; as a result, vital substances like proteins can leak out. This loss of protein is usually accompanied by edema (swelling or puffiness in the feet, ankles, legs, fingers, hands, arms, or eyes), and large amounts of protein in the urine. High cholesterol occurs secondarily, because the liver, in an attempt to produce more proteins, increases lipoprotein synthesis and cholesterol levels.
Lupus nephritis, the technical term for these complications, usually develops within five years after lupus is first diagnosed, and is most often seen in people between the ages of 20 and 40. Both lupus itself and lupus nephritis are more common in Hispanics/Latinos, Asians, and African Americans, like Pruitt, than in other ethnic groups. The disease is also more severe in African Americans. Although lupus is much more common in women, (the female-to-male ratio is nine to one), men with lupus are more likely to get kidney disease and to have a worse prognosis.
Treatment Options
The most common therapies for lupus kidney disease -- such as high doses of steroids and chemotherapy drugs such as cyclophosphamide (Cytoxan®) -- have increased the survival rates of people with lupus kidney disease. However, a percentage of individuals still lose kidney function.
"None of the current or even future therapies have a significant effect upon scarring of the kidney, once it occurs," says James Tumlin, M.D., a nephrologist at Southeast Renal Research Center in Charlotte, N.C. "The truth is that there are many people for whom we have been able to put out the 'fire' of lupus, but we still have to watch a slow smoldering over many years that leads to progressive scarring and loss of renal function."
Tumlin predicts future lupus nephritis research will focus on efforts to block the progression of fibrosis (the formation of excess connective tissue in an organ).
Fibrosis is characterized by the laying down of collagen and other 'scar proteins.' Eventually this material replaces normal tissue and blocks any potential chance for restoration of normal tissue. Tumlin says that several companies are conducting research in this arena today. "In the future, previously damaged kidney tissue may have the potential of reversing renal scarring," he says.
Michael P. Madaio, M.D., chief of nephrology and professor of medicine at Temple University School of Medicine in Philadelphia, notes that doctors in the U.S. and Europe have started using mycophenolate mofetil (MMF; CellCept®) as a primary therapy -- that is, at the start of treatment -- for lupus nephritis. "In these studies, MMF over one to two years seems to be as effective as steroids and chemotherapy drugs, like Cytoxan® (CTX) or maybe more effective, with fewer side effects," he says.
There also are benefits to adding immunosuppressive drugs like MMF, CTX, or Imuran® (azathioprine) to steroids as combination therapy. Citing studies as early as the 1970s, Madaio notes that no difference was found between use of prednisone alone and prednisone with cyclophosphamide in the treatment of lupus nephritis over the short term (e.g. one to two years). However, when patients were followed for four to five years, they had less frequent kidney disease progression to end stage renal disease requiring either dialysis or transplantation. More recently MMF has been shown to be at least as effective over the short term (two years) in preserving kidney function as CTX, with fewer side effects.
There were also few flares requiring re-treatment when MMF is used, which doctors call "the steroid-sparing effect." Certainly steroids are effective in treating the acute bouts of nephritis due to their anti-inflammatory and immunosuppressive effects, but they do have significant side effects. Madaio explains that steroid sparing refers to use of drugs that allow for reduced doses of steroids.
"For example," he says, "treatment with MMF or CTX allows for the quicker taper of high dose steroids (used for treatment of lupus flares), and over the long run limits side effects associated with long-term steroid use. The idea is to treat acute flares with short doses of high dose steroids to treat the inflammation, while adding other immunosuppressives drugs to treat flares and to prevent repeated attacks of disease."
Joan T. Merrill, M.D., head of the Clinical Pharmacology Research Program at Oklahoma Medical Research Foundation in Oklahoma City, and LFA medical advisor, agrees that a number of studies on the effectiveness of MMF in the treatment of lupus nephritis show it is at least as effective as Cytoxan, with fewer side effects.
"I hope some day soon we will have treatments, or combinations of treatments, which will put people into remission in a more reliable way than any of these, and keep them there," says Merrill. "That’s why we are happy to see so many new drugs now being tested for lupus."
Promising New Advances
While 20 years ago there were just a handful of companies working on new drugs to treat lupus, today there are more than 30.
Tumlin believes the future of lupus nephritis management will be new drugs that offer the potential for "resetting" immune tolerance -- "In essence, creating prolonged remissions with a minimum of toxicity," he says.
"A lot of pharmaceutical companies are now paying attention to lupus, and either applying agents to lupus that they have already developed for other uses, or developing agents for lupus specifically," says Madaio. "We have learned much in the past decades from basic research that has led to the development of more targeted therapies, and we are also learning how and when to use these agents. Treating acute flares and keeping patients in remission will likely require different approaches to either reverse the ongoing disease activity or prevent inflammation, while minimizing side effects in each situation."
The drug furthest along in lupus nephritis clinical trials is abetimus sodium (Riquent®), which was developed to target antibodies to double-stranded DNA (anti-dsDNA) that are associated with kidney disease in lupus. Abetimus (uh-BET-ih-muhs) only targets the antibodies associated with kidney disease and so it might only remove the pathogenic antibodies and/or kill the specific B cells that produce those antibodies, leaving all other B cells and all other natural antibodies intact. This is why it is potentially safer than drugs that suppress more of the immune system’s functions.
Riquent has been granted orphan drug status for the treatment of lupus kidney disease by the U.S. Food and Drug Administration (FDA), with Phase 3 clinical trials still underway.
Making Lifestyle Changes
As research into new therapies continues, there are a number of steps patients can take to keep their kidneys healthy as long as possible.
Madaio’s suggestions for lifestyle adaptations are practical for anyone with lupus, whether or not they have nephritis. "You want to avoid the things that could cause a disease flare -- whether that is the sun, a certain food, or stress. And become actively involved in your care. After all, you know your body better than anyone else. It’s better for you to be a pain in the neck about something that might be a new symptom or problem, and to call your doctor about it, than for you not to care," he says.
"At the very least, go to your doctor appointments and stay compliant with instructions and medications," he urges.
Skip Pruitt would probably be Madaio’s ideal patient. But it wasn’t always that way. "To be honest, whenever I have had a flare-up, it was when I was not being diligent with my doctor appointments," Pruitt admits. "In 1994 I was traveling a lot, and I allowed the symptoms to fester. Lupus is very sneaky; You can have a flare-up even when you think everything is going right.
"Now I’m very serious about the discipline of taking care of myself. I work out three times a week, I play golf -- I’m very active, but I get my rest, too, and try to manage my stress. I see my doctor every three months now, and check my blood pressure regularly myself. But if you wait six or nine months to see your doctor, your treatment may have to be radical to get things right again. That’s why it’s best to take a prophylactic approach."
Mary Francolic worries about her kidney disease coming back, although for now she is stable. "I worry as soon as I feel any tightness in my ankles," she admits. "I know that worrying aggravates my lupus, so I try to release my stress by walking for exercise."
"Still, I have been feeling pretty good and I am keeping my fingers crossed that it stays that way."
She and Pruitt both follow doctors’ instructions about limiting their salt intake, but neither has had a doctor warn them against too much protein in their diet.
"As for me, other than a small amount of protein loss that persists, my kidney disease is inactive; I take only Plaquenil and Naprosyn for my lupus. March 2007 was the 14-year anniversary of my lupus nephritis diagnosis, and I feel great. I am one of the lucky ones."