Lupus is a prominent name among the myriad chronic inflammatory conditions where the body’s immune system begins attacking its own tissues. This autoimmune condition can impact virtually any organ of the body.  It is incurable, the clinical presentation is widely variable with sometimes debilitating flares and the complications, potentially fatal in some cases when left untreated. Among other organs, Kidneys are a prime target here. So, as a portal dedicated to nephrology, let us walk you through the what-why-how of this challenging autoimmune disorder with specific focus on Lupus Nephritis – its kidney chapter. It is Lupus Awareness Month (May) after all!

We will first start with a brief insight into the parent condition namely Systemic Lupus Erythematosus (SLE) for a head-start, before we delve into the specifics of Lupus Nephritis.

What is Lupus?

Systemic Lupus Erythematosus (SLE) or Lupus is a chronic, inflammatory autoimmune disorder impacting multiple organs, most commonly being the skin, bone joints, kidneys, blood cells, brain, heart and lungs. It derives its name from its multi-organ involvement (hence Systemic) and its characteristic red rashes [erythematosus = erythros (Greek) for red] on the skin that resemble a healing wolf-bite wound [Lupus = Latin for Wolf)].

Here, the aberrant immune system attacks the cells of its own organs, with antibodies specifically directed against the gene core called the nucleus and the supporting jelly containing all cellular machinery surrounding the nucleus, known as the cytoplasm. Why this happens is a subject of active research. But scientists at University of Washington, Seattle have observed that in patients with SLE, the routine ability of their bodies to clear out dead cells slows down. As a consequence, the immune system gets hyperactive and “decides to acquire” necessary machinery to help out with the dead-cell purging. This machinery is in the form of antibodies directed against the nucleus and cytoplasm of cells. Specifically, these are known as Anti-nuclear Antibody (ANA) and Anti-neutrophil Cytoplasmic Antibody (ANCA). Among other diagnostic markers, doctors look for these antibodies in your blood-work if they suspect you have Lupus.

Depending on the organ or combination of organs, Lupus can produce diverse clinical manifestations as listed here. Its presentation and course are highly variable, ranging from inert & insidious to acute, severe and extensive. Since it is chronic in nature, it displays a relapsing and remitting course. This means, clinically-approved medication can slow down the tissue damage in Lupus but flare-ups may occur if triggers as listed below surface. Over 90% of cases occur in women, frequently between ages 15-44 years.

What causes Lupus?

The exact cause of Lupus / SLE remains unknown. However, clinical presentations commonly draw an association with the following:

1. Genetic predisposition (running in the family)
2. Environmental factors (like overexposure to sunlight, photo-sensitivity or industrial pollutants like Silica dust)
3. Hormonal factors (women in child-bearing age group are frequent)
4. Certain medications (Anti-TB drugs and some psychiatric meds)

Signs and symptoms

Common clinical manifestations in SLE patients may include the following [1] :

• Fever

• Butterfly-shaped rash on the face that covers the cheeks and bridge of the nose or rashes elsewhere on the body

• Skin lesions that appear or worsen with sun exposure

• Joint pain, stiffness and swelling

• Fingers and toes that turn white or blue when exposed to cold or during stressful periods (Raynaud’s Syndrome)

• Dry eyes

• Mouth ulcers

• Shortness of breath
• Chest pain
• Headaches, confusion and memory loss

Doctors consider investigating for SLE if any woman of child-bearing age group (15-44 years) presents with the classic triad of fever, joint pain, and rash. [2, 3]

LUPUS NEPHRITIS

Lupus Nephritis is the technical name for manifestations of SLE arising out of impact of the inflammatory disease process on Kidneys. The kidney is the most common target visceral organ in SLE. This does not mean all patients with Lupus end up with kidney failure. Statistically, approximately 50% of patients with SLE develop clinically evident kidney disease. However, biopsy studies show some degree of renal involvement in most SLE patients, whether clinically evident or not. Therefore, your doctor would carefully classify the extent of kidney involvement to help you understand the likely kidney disease course in your case. 

Lupus is often asymptomatic in the initial years. But evaluating kidney function in SLE patients is important because early detection and treatment of renal involvement can significantly improve clinical outcome in terms of kidney disease.

Symptoms

Patients with lupus nephritis may report other symptoms of active SLE as illustrated here; these are more common with focal and diffuse lupus nephritis.

Asymptomatic Lupus Nephritis

As the name suggests, “asymptomatic” lupus nephritis means the patient does not have any clinical signs or symptoms suggestive of Lupus. It is only evident during regular follow-ups when Urine Routine Examination (URE) could show the presence of blood and/or protein in Urine. This is typical of mesangial or membranous nephritis.

Active Nephritis

Active Nephritis is the clinically evident version of Lupus Nephritis. It can manifest in either of the following ways:

1. Acute Kidney Injury   
2. Chronic Kidney Disease 
3. Nephrotic Syndrome 

Acute Kidney Injury is typical of Diffuse Lupus Nephritis. It presents with signs and symptoms of poor renal function such as:

• Fluid retention in dependent parts of the body (Edema)
• Raised blood pressure (Hypertension)
• Headache and dizziness
• Nausea and vomiting

On the other hand, Nephrotic syndrome seen in Membranous Lupus Nephritis presents with symptoms related to protein leak in urine such as:

• Fluid retention in dependent parts of the body like ankles, around eyes, lungs, heart or belly
• Problems with blood clotting

Diagnosis

Laboratory tests to evaluate renal function in SLE patients include the following:

1. Blood urea nitrogen (BUN) testing
2. Serum creatinine assessment
3. Urinalysis (to check for protein, red blood cells [RBCs], and cellular casts)
4. Spot urine test for creatinine and protein concentration
5. 24-hour urine test for creatinine clearance and protein excretion

Laboratory tests for SLE disease activity include the following:

1. Antibodies to double-stranded DNA (dsDNA)
2. Complement (C3, C4, and CH50)
3. Erythrocyte sedimentation rate (ESR)
4. C-reactive protein (CRP)

Note: Any SLE patient who has clinical or laboratory evidence of active nephritis is a candidate for Kidney Biopsy, especially upon the first episode of nephritis.

Treatment

The chief aim of therapy in lupus nephritis is to halt kidney damage to normalize kidney function or at least, to slow down the progressive loss of renal function. Therapy differs, depending on the extent and type of pathologic lesion as listed in the table below.

Guidelines issued by the American College of Rheumatology for managing lupus nephritis are as follows:

• Patients with clinical evidence of active, previously untreated lupus nephritis should have a kidney biopsy to classify the disease according to ISN/RPS criteria as below:

• All patients with lupus nephritis should receive background therapy with Hydroxychloroquine, unless contraindicated.
• Glucocorticoids (Eg: Prednisone) plus either cyclophosphamide (Endoxan) intravenously or mycophenolate mofetil (Cellcept) orally should be administered to patients with class III/IV disease; patients with class I/II nephritis do not require immunosuppressive therapy
• Angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers should be administered if proteinuria reaches or exceeds 0.5 g/day
• Blood pressure should be maintained at or below 130/80 mm Hg

Patients with class V lupus nephritis are generally treated with Prednisone for 1-3 months, followed by tapering for 1-2 years if a response occurs. If no response occurs, the drug is discontinued. Immunosuppressive drugs are generally not used unless renal function worsens or a kidney biopsy shows a “proliferative” component.

What’s New in the treatment block?

Yes. These include the following:

• Voclosporin – This belongs to the class of Calcineurin Inhibitors that works by blocking T-lymphocyte (immune cell) activity. It is approved for use in conjunction with  immunosuppressive therapy.
• Belimumab, an anti–B-lymphocyte stimulator [BLyS] monoclonal antibody, which is approved for treatment of adults with active lupus nephritis who are receiving standard therapy

Therapies under Investigation for Lupus Nephritis:

1. Rituximab
2. Other anti-CD20 monoclonal antibodies (eg, ocrelizumab, ofatumumab, epratuzumab, and TRU-015)
3. Atacicept
4. Abetimus
5. Anticytokine therapies (eg, monoclonal antibodies directed against interferon alfa, interleukin [IL]-1, IL-6, IL-10, and tumor necrosis factor alpha [TNF-α])

Patients with end-stage renal disease require dialysis and are good candidates for kidney transplantation. Where patients start dialysis first, hemodialysis is preferred to peritoneal dialysis.