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Lupus Nephritis: An Overview

An Interview with Kyriakos A. Kirou, MD, DSc, FACP

Joint pain and swelling, skin rash, fatigue and fever are often the primary manifestations of systemic lupus erythematosus (SLE), but people with this autoimmune condition face a variety of health challenges that affect other organs, including the heart and lungs. Between 30-50% of those diagnosed with SLE develop kidney disease or lupus nephritis.

In people with lupus, the immune system mistakenly regards its own tissues as foreign substances, setting off a response intended to protect the body. Inflammation occurs as special cells called lymphocytes along with other chemicals are sent to kill and clean up these “invaders.” In otherwise healthy people, inflammation is a normal and temporary part of the immune response. However, in a person with SLE or other types of autoimmune disease, inflammation can become chronic, resulting in damage to joints or organs.

Although autoimmune diseases like lupus can affect all parts of the body, the kidneys may be particularly vulnerable to damage as structures called immune complexes (a combination of an antibody and the ostensibly “foreign material” it is combating) develop and deposit in the kidneys. Once there, they cause both inflammation and alterations in the anatomy of the kidney that result in the loss of protein and/or blood cells in the urine. Of note, each kidney is composed of about 1 million functional units, called nephrons, it’s functional units. Each nephron is made of a glomerulus (glomeruli in plural) where the blood is filtered and the tubules that receive the filtrated portion of the blood along with waste body products and excrete it as urine. The vessels in the glomerulus that filter waste out of the blood are porous and permit the immune complexes to enter the kidney tissues and cause kidney inflammation (nephritis).

In the individual with lupus nephritis, both kidneys are always affected. In a healthy individual, the kidneys effectively filter the blood removing any toxins or other waste materials. They also play a role in maintaining blood pressure.

For reasons that are not yet fully understood, women develop SLE far more frequently than do men (at a ratio of 9:1) and women of African-American, Asian and Hispanic descent are at greater risk than their Caucasian counterparts, which suggests a genetic cause. The disease usually occurs during the reproductive years. Similarly, lupus nephritis is seen more frequently in women.

Moreover, lupus nephritis usually develops in people with more severe forms of SLE, says Kyriakos A. Kirou, MD, Clinical Co-Director, Mary Kirkland Center for Lupus Care at Hospital for Special Surgery (HSS). 

Symptoms and signs of lupus nephritis can include swelling or puffiness of the feet, legs and eyes; high protein levels in the urine; frothy or frequent urination; blood in the urine; and high blood pressure.


In addition to conducting a thorough physical examination and patient history, rheumatologists, doctors who specialize in the treatment of autoimmune disorders, use a wide range of tests to assess kidney function. These include measuring creatinine - a waste product related to normal tissue breakdown, as well as levels of certain antibodies and other proteins in the blood and urine. The presence of high levels of anti-DNA antibodies, and lower than normal levels of proteins called Complement 3 and Complement 4 not only help to confirm a diagnosis of lupus but also appear to indicate an increased risk of developing lupus nephritis, according to Dr. Kirou.

Many other additional laboratory values are also assessed to give the rheumatologist and other physicians involved in the patient’s care the “big picture” of how lupus nephritis and its treatment may be affecting other systems and organs. These include measurements of lipids, blood sugar, albumin, blood counts, and bone mineral density. Learn more about testing for lupus nephritis.

Additional tests, such as a renal ultrasound, may be needed to exclude other kidney problems that may need a different treatment than lupus nephritis. “Before beginning treatment, it’s very important to determine that the patient’s kidney problems are being caused by lupus nephritis and not by another condition such as an infection or an obstruction like a kidney stone,” says Dr. Kirou.

If the physician suspects that lupus nephritis is causing the symptoms and abnormal laboratory results, he or she will often also recommend a biopsy. In this procedure, which is usually performed by a nephrologist using a special needle under ultrasound or other radiographic guidance, a small piece of tissue is removed from the kidney. Biopsies reveal whether any changes have occurred in the cells of the kidney and whether there is any scarring present. [Figures 1A and 1B] Information gathered with a biopsy is an important tool in determining the course of treatment.

Figure 1A (left): Kidney biopsy showing a normal glomerulus.
Figure 1B (right): Kidney biopsy from a patient with class IV lupus nephritis showing a glomerulus
with narrowing/closing of the capillaries (small blood vessel) from an abnormal increase of cells within those vessels.

Lupus Nephritis Classification

Lupus nephritis is diagnosed according to the 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification of lupus nephritis:

  • Class I, also called minimal mesangial lupus nephritis
  • Class II, also called mesangial proliferative lupus nephritis

Both Class I and Class II are mild forms of the disease that do not require treatment.

  • Class III, focal lupus nephritis
  • Class IV, diffuse segmental (IV-S) or global (IV-G) lupus nephritis

Class III and Class IV are serious forms of the disease, with the two types of Class IV being more aggressive than class III.

  • Class V disease, or membranous lupus nephritis may occur by itself or in combination with class III or class IV.

When it Class V occurs by itself, it can take two forms depending on whether the individual has nephrotic proteinuria (the presence of high levels of protein in the urine) or non-nephrotic proteinuria.

  • Nephrotic proteinuria is defined as protein loss of 3.5 grams or greater over a 24-hour period; this condition is may be associated with a higher risk of developing blood clots.
  • Class V nephritis with non-nephrotic proteinuria is a less severe condition in which the loss of protein through the urine is less than 3.5 grams over a 24-hour period.

In the case of classes III and IV, the biopsy will also indicate the proportion of glomeruli with inflammation (active) and with scar tissue (sclerotic). The presence of more aggressive forms of inflammation such as “crescents” and “fibrinoid necrosis” will also be indicated.

In all classes, the biopsy comments on the presence, type, and degree of tubular, interstitial (the tissue between kidney units) and vascular involvement. 

If a person is found to have Class VI disease, or advanced sclerosing lupus nephritis, the kidney contains only scar tissue without active inflammation, and therefore aggressive treatment with immunosuppressive drugs is not indicated. Patients with this type of lupus nephritis will not benefit from medication and are started on dialysis.

“Up to 20% of patients with lupus nephritis eventually require a transplant,” Dr. Kirou adds. “This percentage is the average and includes people not optimally treated.”


People with the more severe forms of lupus nephritis, classes III, IV and V (with nephrotic proteinuria), need to be started on an aggressive course of treatment that is also referred to as induction therapy, since the goal is induce a remission of the inflammation and related symptoms. During induction therapy, a period that usually lasts for six months, immunosuppressive drugs are administered at high doses. A key point here is to start induction therapy as soon as possible without losing time, in order to minimize loss of kidney tissue from the inflammation.

“Time is kidney,” Dr. Kirou emphasizes. As the condition improves, the patient switches to maintenance therapy, in which a lower dose of the drug or drugs is administered. Maintenance therapy continues for at least 2 years, although the optimal duration is not known yet.

Because immunosuppressive agents are powerful drugs with the potential for serious side effects, the rheumatologist strives to taper their use as soon as the condition allows.

Immunosuppressive agents include:

  • High dose glucocorticoids (or steroids) such as prednisone (by mouth) or methylprednisolone administered by mouth, often after IV infusions of methylprednisolone for 1-3 days
  • Intravenous administration of cyclophosphamide every month for a period of six months
  • Oral mycophenolate
  • Oral azathioprine
  • Other agents that may occasionally be used include: cyclosporine, tacrolimus, rituximab, etc

Adjunctive therapy that addresses other disease-related concerns may include one or more of the following, depending on the individual case and if there are no contraindications:

  • Diuretics, to reduce swelling and control blood pressure
  • Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs), additional drugs that help control high blood pressure and reduce proteinuria
  • Bisphosphonates to protect the bones
  • Statins and other drugs that control cholesterol
  • Anticoagulants for people at risk of blood clots
  • Oral antibiotics and vaccines to protect against microbial infections such as pneumonia or the flu

Initially, some people with very severe lupus nephritis may need to be hospitalized while receiving treatment. This is done to ensure that any complications of the disease or treatment can be addressed promptly. However, many people with lupus nephritis are able to receive specific treatment including therapeutic infusions on an out-patient basis. 

Treatment for lupus nephritis can be complicated. Both lupus itself and the drugs taken to manage the disease can put the patient at greater risk of infection, cardiovascular disease, risk of stroke, osteoporosis, and weight gain. Glucocorticoid (steroid) therapy alone is associated with many adverse effects such as weight gain, osteoporosis, and osteonecrosis (bone damage that may lead to severe arthritis of the hip and need for surgery). 

“Our goal with treatment is to control the disease as quickly as possible, and then reduce the dose of medication given, to limit side effects,” says Dr. Kirou. Fortunately, he notes, younger patients are usually better able to tolerate immunosuppressive drugs, and lupus primarily affects this younger population, “Many patients show rapid improvement with induction therapy.”

People undergoing treatment for lupus nephritis are also advised to follow various guidelines regarding diet, nutritional supplements, and over-the-counter drugs. All patients will need to limit the amount of salt in their diet, and some may need to restrict the amount of protein they consume. If they are taking prednisone, which can increase the risk of osteoporosis, it’s important to supplement the diet with calcium and vitamin D. People with lupus nephritis should eat a healthy diet, maintain a healthy weight and avoid taking non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, which place further stress on the kidneys. They should also avoid the IV contrasts that are administered with some CT scans and MRIs, unless they are absolutely necessary.

In addition to physical challenges, a diagnosis of lupus nephritis can also take a psychological toll. For those having difficulty coping, family support and social work services may help.

“Many patients with the disease are young women who may be thinking of starting a family,” Dr. Kirou says. “If lupus nephritis is active, pregnancy is not just inadvisable, but can be life-threatening.” However, he adds, in cases where treatment results in a period of quiescence or inactivity for six months, without much kidney damage, and with careful adjustment of medications, a safe pregnancy is the rule. Patients who undergo successful transplants are also able to become pregnant.

In many people, timely and aggressive treatment of lupus nephritis results in considerable improvement and, often complete, remission of the disease and its symptoms. But treatment is not yet optimal for all patients with lupus nephritis, according to Dr. Kirou.  People who do not respond to conventional treatment may be eligible for clinical studies of newer agents.

Unfortunately, people who are successfully treated for lupus nephritis remain at risk of recurrence for the condition. Therefore, regular monitoring of kidney function is essential, especially since the early signs of recurrence may only be detectable with laboratory tests. Dr. Kirou advises all people with lupus nephritis to see their doctor at least every three months for follow-up.

Looking to the Future

Researchers and physicians at HSS and across the country continue to evaluate the possible role of other medications to effectively treat lupus nephritis and minimize the risk of side effects. Some of the biologic agents that are used to treat rheumatoid arthritis, another autoimmune disease, represent one area of interest. Other drugs are also being studied for lupus nephritis.

To further refine and improve care for people with lupus nephritis, Dr. Kirou and his colleagues at HSS have established a registry designed to collect information on treatment outcomes. This is part of a collaborative effort with other medical centers.

To optimize their care, Dr. Kirou advises all patients with lupus nephritis to work closely with their physicians, ask many questions, and take their medicines as directed. “This can be a difficult diagnosis to accept,” he acknowledges, “but those who do, will have a better outcome than those who don’t address the problem.”

At the Lupus and APS Center of Excellence at HSS, people with lupus nephritis benefit from multidisciplinary care from a team of rheumatologists, nephrologists, pathologists and other specialists, an on-site infusion service, social work and other support services in a single location. Many of the Center’s faculty members are also engaged in clinical research designed to improve treatment outcomes. Please visit our Lupus Nephritis Program page for more information.

If you would like more information about the treatment of lupus nephritis at HSS, please visit the Physician Referral Service or call 1.877.606.1555.


We thank our trusted colleague, Dr. Surya V Seshan, Professor of Clinical Pathology and Laboratory Medicine at Weill Cornell Medical College, for her kind provision of the kidney biopsy pictures in this article and her helpful comments.

Summary by Nancy Novick


Headshot of Kyriakos A. Kirou, MD, DSc, FACP
Kyriakos A. Kirou, MD, DSc, FACP
Director, Lupus Nephritis Program, Hospital for Special Surgery
Clinical Co-Director, Mary Kirkland Center for Lupus Care, Hospital for Special Surgery

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