Lupus and Kidney Disease: What You Should Know about Lupus Nephritis (Lupus Kidney Disease)

Introduction

At this session of the SLE Workshop at HSS, Dr. Kyriakos Kirou presented his expertise on the diagnosis, symptoms, treatments, and research related to lupus and kidney involvement, including lupus nephritis (LN). Dr. Kirou is an assistant attending physician at HSS and the co-director of the Mary Kirkland Center for Lupus Care.

When presenting, Dr. Kirou emphasized that the purpose of his presentation is to educate patients about lupus and its interaction with the kidney and should not be used as therapeutic advice. He stressed that when patients need to make a decision about their own specific care, they should consult their own rheumatologist. It is important to recognize that there’s no “one fits all” therapy.

Dr. Kirou discussed how lupus can affect the kidney and cause the disease known as lupus nephritis (LN). He also discussed tests that are used for diagnosis, as well as available therapies. He also spoke about the necessary lifestyle changes that LN patients may have to adopt after their diagnosis of LN to minimize harm in their bodies.

First, it is important to understand how the kidney functions, what happens when someone with lupus has problems with their kidneys, and how they can go about dealing with the situation.

Background Information

Lupus:
Lupus is a chronic and autoimmune disease that affects several parts of the body, including joints, blood, skin, and kidneys. The immune system of those with lupus does not function properly. Lupus creates autoantibodies that fight and damage the cells, tissues, and body organs. When they are present, they can likely lead to disease.

Kidney:
The kidney is a bean-shaped, fist-sized organ that helps cleans the body from any toxic or other waste products. In addition, the kidney plays an important role in helping to maintain blood pressure, the volume of body fluids, and the body's water and PH balance. We have two kidneys, but one healthy kidney could be sufficient for our needs. As we get older, we start to lose some of our kidney function.

Lupus Nephritis

Lupus Nephritis (LN) is the disease of the kidneys due to lupus. This occurs when lupus autoantibodies deposit in the kidneys and cause inflammation. About 30-50% of lupus patients will develop LN within the first six months to three years of being diagnosed with SLE. Inflammation of the kidney prevents it from functioning normally and can cause it to spill protein, which causes frothy and/or bloody urine. Other early manifestations of lupus nephritis include swelling of the feet and an increase in blood pressure. These symptoms are usually seen as the first signs of the disease. 

Signs of LN may include:

• Swelling or puffiness of feet, legs, eyes
• High blood pressure
• Frothy urine or getting up constantly to urinate at night
• Blood in urine

One may not experience any symptoms, however, so a urine test is needed. It’s crucial to have your doctor rule out other causes such as kidney stones or a urinary infection before considering the diagnosis of LN.

WHO (World Health Organization) Lupus Nephritis Classification:

Class 1: Minimal Mesangial Lupus nephritis (LN)
Class 2: Mesangial Proliferative LN
Class 3: Focal Proliferative LN
Class 4: Diffuse Proliferative LN
Class 5: Membranous LN

Kidney biopsy is crucial to help diagnose lupus nephritis and rule out other issues. It’s also helpful to identify the class of LN in a given case in order to determine the most effective therapy for that patient.

A biopsy is performed whenever there’s an indication of a severe form of nephritis (Class 3-5). At times, especially when the disease does not respond well to therapy or there is a new flare, the biopsy will need to be repeated to assess intensity of inflammation and degree of scarring. If scarring is the main finding of the biopsy (often classified as class VI or Advanced sclerosing LN according to more recent classification systems), aggressive therapy is unlikely to be helpful and may need to be discontinued in order to avoid unnecessary toxicity.

Testing for Lupus Nephritis

There is a wide range of tests that can determine how the kidney is affected.

1. Blood: BUN (normally<20) and creatinine (Cr; normally <1 in average woman; it may be higher in muscular men as it reflects muscle mass). Also albumin (normal>3.5) which may be decreased due to loss of protein in the urine.
2. Electrolytes: sodium, potassium, bicarbonate
3. Creatinine clearance: Calculated by using creatinine, age, race, gender. Normally 80-120 ml/min/1.73m2
4. Urine analysis: Normally 0-trace protein, no red and white blood cells (<5 RBC, <5 WBC)
5. 24-h urine protein: (creatinine is also measured to assess whether collection was performed properly): normally <300mg/24h. In lupus by definition>500 mg/24h. 
6. Spot urine protein/creatinine ratio: Normally <300 mg/24h. It may vary depending on the timing of collection: best to test second urine of the day
7. Renal ultrasound: size of kidneys and consistency of kidney tissue
8. Kidney biopsy

Other Important Tests:

1. Serology:

1. C3 (normally>80), when disease is active, it is usually low
2. C4 (normally>18), when disease is active, it is usually low
3. Anti-dsDNA (normal is 0), when disease is active, it is usually high
4. Antiphospolipid antibodies (anticardiolipin antibodies IgG, IgM, IgA, and lupus anticoagulant). This might determine whether blood thinners are needed

2. Bone tests:

1. Blood level of 25-OH-Vitamin D (normal >30 ng/ml)
2. Blood level of intact parathyroid hormone (iPTH; it is usually high in advanced kidney disease or with low 25-OH-Vitamin D levels)
3. Bone mineral density test (to check for osteoporosis)

3. Fasting lipids: High in nephrotic syndrome

4. Fasting blood sugar: Diabetes or other complications of steroids

5. Hemoglobin (HB): Anemia might be due to the inflammation, blood loss, hemolysis, or advanced kidney disease.

6. White blood cells: Low due to the disease or therapy. Increased risk of infection.

7. Platelets (PLT): Low due to the disease or therapy. Increased risk of bleeding.

8. Purified protein derivative (PPD) test for latent tuberculosis (TB)

9. Hepatitis C, Hepatitis B, HIV

Therapy of Lupus Nephritis

In proliferative lupus nephritis (severe class III or class IV), aggressive immunosuppressive therapy is required without delay to “calm down” the overactive immune system. This is called induction therapy, as it aims to induce remission. There are many types of induction therapy, but typically all require a high dose of glucocorticoids (such as Medrol or Prednisone) plus one of the following:

1. Chemotherapy (IV cyclophosphamide every month for six months)
2. Oral Cellcept (mycophenolic acid)

After about six months of induction therapy and hopefully a good response or remission of the disease, we apply maintenance of remission therapy to maintain remission and avoid a new flare of the nephritis. In this case we typically use only a low dose of glucocorticoids, or none at all, plus one of the following options:

1. Oral Cellcept (mycophenolic acid)
2. Oral Imuran (azathioprine)

For both induction and maintenance therapies, patients may consider enrolling in clinical trials of new promising therapeutic agents. This is a consideration since available conventional therapies at present are not optimal with regard to either efficacy or safety.

Addressing Comorbidity (associated health issues)

Although induction therapy and maintenance of remission therapy comprise the main strategy we use to suppress kidney inflammation in patients with lupus nephritis, additional therapies are needed for optimal results:

1. Antihypertensives: These are needed to control the often very high blood pressure of these patients as a result of LN:
   1. Angiotensin Converting Enzyme inhibitors (ACEI)
   2. Angiotensin Receptor Blocker (ARB)
   3. Diuretics (Lasix)
      Note: ACEI and ARB agents are also effective in decreasing the amount of protein spilled in the urine, independently of the immunosuppressive therapies indicated above.
2. Bone Protection: The following agents are needed to protect the bones from osteoporosis and fractures that may occur as an adverse event from therapy with glucocorticoids.
   1. Calcium (about 1500 mg of calcium per day) + Vitamin D3 (at least 1000 units per day; higher doses may be required if the blood test shows a low level).
   2. Bisphosphonates (Fosamax, Actonel, Boniva, etc.), if there are no contraindications to their use. In some cases with severe osteoporosis, doctors would use Forteo (teriparatide, a form of parathyroid hormone).
3. Lipid Reduction: These agents are often needed to protect from atherosclerosis and its consequences (heart attack, stroke, etc.) in the long term.
   a. Statins are usually used (if there are no contraindications).
4. Anticoagulation agents are used when there is a high risk of blood clots as it might occur in the antiphospholipid and nephrotic syndromes
5. Vaccines such those below with antigens from inactivated infectious agents are used to protect from infections while the immune system is suppressed with LN therapy. Please note that vaccines with live viruses (such as the MMR, oral polio, shingles, nasal influenza vaccine preparations) are contraindicated when the immune system is suppressed.
   1. Influenza
   2. Pneumonia

Some lifestyle changes that can be very important in protecting the kidneys include:

• Being hydrated 
• Maintaining a low sodium intake, especially if one has hypertension 
• Maintaining a low potassium intake, low phosphorus, low protein (for patients with already diminished kidney function)
• Maintaining a low cholesterol diet 
• Don’t smoke or drink alcohol 
• Exercise 
• Maintain your blood pressure and weight 
• Avoid nephrotoxic agents such as NSAIDS (Advil, Aleve) and so forth.

Conclusion and Important Take-Home Messages

• Be active in your health care and partner with your rheumatologist and nephrologists (doctor who specialize in kidney diseases) 
• Be aware of what pills you’re taking, their dosage, and when to take them.
• Recognize the different signs of flares relating to the disease, such as headache, high blood pressure, discolored urine, fever, joint pains, skin rash, shortness of breath, and foot/eye swelling. Notify your doctors.
• Recognize the signs of potential drug adverse events such as fever, chills, sore throat, cough, shortness of breath, blood in urine and diarrhea. Notify your doctors.
• Do not ignore your bone health (having enough calcium/vitamin D) or cardiovascular health (i.e., smoking, low cholesterol diet)

Updated: 2/27/2010

Summary by Lay Tep, SLE Workshop Coordinator and Social Work Intern

Authors

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