Lupus nephritis: A complex autoimmune challenge
May 8, 2025
Systemic lupus erythematosus (SLE) is an autoimmune disorder where the body's immune system mistakenly attacks its own tissues. This occurs due to the formation of abnormal antibodies that target healthy cells, leading to inflammation and damage in various organs.
Systemic lupus erythematosus (SLE), commonly known as lupus, is a chronic autoimmune disease that can affect almost every organ in the body. The term "lupus" comes from the Latin word for wolf, named so because the facial lesions seen in early cases resembled a wolf's bite. The word "erythematosus" signifies redness, reflecting the characteristic rash often seen in lupus patients.
What is systemic lupus erythematosus? SLE is an autoimmune disorder where the body's immune system mistakenly attacks its own tissues. "This occurs due to the formation of abnormal antibodies that target healthy cells, leading to inflammation and damage in various organs," explains Professor Dr Rozita Mohd (pix), a Senior Consultant Physician and Nephrologist at Hospital Tuanku Muhriz Universiti Kebangsaan Malaysia (HCTM UKM). SLE can occur at any age but predominantly affects young adults between the ages of 25 and 35. Notably, it is more common in women, with a ratio of 9 females to 1 male. Additionally, lupus is more prevalent among Asians and Black individuals compared to Caucasians. A study at UKM found that SLE often follows a relapsing-remitting pattern, where periods of disease activity are followed by remission. Genetic factors, environmental triggers, and hormonal influences are significant in the disease's onset and recurrence. Living with lupus: Symptoms and challenges Patients with SLE experience a wide range of symptoms, including fatigue, joint pain, skin rashes, and organ-specific complications. The disease's unpredictable nature makes management challenging. During flares, the immune system becomes overactive, leading to symptoms such as high fever, mouth and nose ulcers, pleuritis, pneumonitis, pulmonary emboli, and even severe abdominal pain. One common presentation is the characteristic "butterfly rash" across the cheeks and nose, often mistaken for a sunburn. Patients may also experience hair loss, anemia, high blood pressure, and musculoskeletal pain. The condition can even affect the heart, leading to endocarditis, atherosclerosis, or pericarditis. Lupus nephritis: A major complication Lupus nephritis is a severe manifestation of SLE that specifically targets the kidneys, leading to inflammation and potential renal failure. Symptoms include frothy urine, leg swelling, and high blood pressure. In advanced cases, patients may develop blood in the urine or require dialysis. Diagnosis of lupus nephritis typically involves urine tests, blood tests, kidney ultrasound, and renal biopsy. According to Dr Rozita, "Sometimes, there is SLE in the kidneys. We also assess the severity to decide on treatment." Diagnosis and classification criteria Over the decades, the classification criteria for SLE have evolved, including the ARA, ACR, SLICC, and the most recent EULAR/ACR 2019 guidelines. These criteria help clinicians diagnose lupus with greater specificity by requiring evidence from both clinical and immunological findings. Diagnosing lupus nephritis typically involves a series of tests to evaluate kidney function and detect abnormalities. These tests include urine analysis, such as a 24-hour urine collection to measure protein levels and assess kidney filtration. Blood tests, particularly blood urea nitrogen (BUN) and creatinine levels, are conducted to evaluate how well the kidneys are filtering waste from the blood. Renal biopsy A renal biopsy is a critical step to confirm the diagnosis of lupus nephritis. It allows for a detailed assessment of the kidney tissue, identifying active inflammation or chronic damage, which informs treatment decisions and prognosis. The biopsy also helps to rule out other potential causes of renal involvement in patients with systemic lupus erythematosus (SLE), such as thrombotic microangiopathy or lupus podocytopathy. One of the main reasons for conducting a renal biopsy is to determine the degree and nature of kidney involvement. The severity can vary greatly, ranging from mild, localized inflammation to widespread, chronic damage. The biopsy helps determine whether the kidney involvement is purely active inflammation, a combination of active and chronic changes, or mainly chronic scarring. By analyzing the tissue under a microscope, healthcare providers can identify the specific stage of lupus nephritis, which is essential for deciding the most appropriate treatment plan. Expert Insight According to Dr Rozita, diagnosing lupus nephritis involves more than just confirming the presence of SLE in the kidneys. “Sometimes, SLE affects the kidneys directly. In addition to confirming the diagnosis, we aim to determine how severe the kidney involvement is. Is it an acute flare or a chronic change? Are the kidneys entirely affected, or is it just a minor impact? We also need to exclude other potential causes that might be affecting the kidneys.” After the biopsy, the tissue sample is examined under a microscope. The pathologist classifies the stage of kidney involvement, as lupus nephritis can present in different forms, from mild to severe. The classification ranges from stage 1 to stage 6, and treatment strategies differ significantly based on the stage. “That’s why we perform a biopsy — to diagnose accurately and tailor the treatment according to the specific class of lupus nephritis,” she explains. ISN/RPS classification of lupus nephritis (LN) Lupus nephritis is classified according to the International Society of Nephrology (ISN) and the Renal Pathology Society (RPS) criteria. The classification system helps categorize the extent of kidney damage and guides treatment decisions. Class I: Minimal mesangial LN Normal light microscopy (LM) but with positive immunofluorescence deposits. Class II: Mesangial proliferative LN Mild changes with mesangial hypercellularity and expansion. Class III: Focal LN (Affecting <50% of all glomeruli) III (A): Active lesions, indicating focal proliferative changes. III (A/C): Mixed active and chronic lesions. III (C): Chronic inactive lesions with evidence of scarring. Class IV: Diffuse LN (Affecting ≥50% of all glomeruli) IV-S (A): Active diffuse segmental proliferative changes. IV-G (A): Active diffuse global proliferative changes. IV-S (A/C): Mixed active and chronic segmental lesions. IV-G (A/C): Mixed active and chronic global lesions. IV-S (C): Chronic inactive segmental lesions with scarring. IV-G (C): Chronic inactive global lesions with scarring. Class V: Membranous LN Characterized by thickened glomerular capillary walls. Class VI: Advanced sclerotic LN More than 90% of glomeruli are sclerosed, indicating severe, irreversible damage. Treatment implications According to Dr Rozita, classes 3, 4, and 5 often require more aggressive treatment. “If a patient is diagnosed with class 3 or 4 combined with class 5, we need to administer intensive therapy to manage the disease effectively. While experience allows us to estimate the patient’s condition, tissue diagnosis remains essential for accurate treatment planning,” she notes. When the biopsy indicates class 6, it signifies advanced sclerosis, meaning the kidneys have suffered significant, possibly irreversible damage. At this point, the focus may shift from aggressive treatment to managing symptoms and preserving any remaining kidney function. “If we observe any viable cells during the biopsy, it helps guide the treatment. For instance, class 1 often appears normal, while class 2 shows subtle changes. Class 3 indicates significant activity, possibly progressing to class 4. By the time we reach class 6, most of the damage is already done, appearing primarily as scarring. Understanding these differences allows us to choose the most appropriate therapeutic approach.” Treatment of lupus nephritis Managing lupus nephritis (LN) can be quite complex, as treatment options vary significantly depending on the severity and progression of the disease. There is no single, universal treatment for lupus nephritis, as each patient’s condition requires a tailored approach. The primary goal of treatment is to control inflammation, prevent further kidney damage, and maintain kidney function for as long as possible. The role of steroids Steroids remain a cornerstone in the treatment of lupus nephritis due to their potent anti-inflammatory and immunosuppressive properties. Steroids can be administered either orally or through injection, depending on the urgency and severity of the condition. When a patient presents with active lupus nephritis, they often require high doses of steroids to quickly suppress inflammation. In severe cases, doctors may start with an intravenous (IV) injection, especially when the disease is very active. The IV treatment typically lasts for a short period — about three to five days. Some medical centers calculate the steroid dose based on the patient's body weight, generally prescribing around 1 mg of steroid per kilogram. For instance, a patient weighing 60 kg would receive approximately 60 mg of steroids. In practice, the difference between initiating treatment with oral steroids versus IV administration is minimal, and the choice often depends on the hospital’s protocol. While steroids are highly effective, they can also have significant side effects, especially when administered in high doses. Therefore, it is essential for patients to follow medical advice carefully to minimize the risks associated with long-term steroid use. Balancing benefits and risks Taking large doses of steroids can lead to various side effects, including infection, weight gain, swelling, blurry vision, insomnia, acne, increased hair growth (hirsutism), mood changes, easy bruising, and high blood pressure. Chronic use may also result in obesity, type 2 diabetes, muscle atrophy, avascular necrosis (bone death), and osteoporosis. Therefore, managing steroid use requires a balanced approach — using enough to control the disease without causing additional health problems. Glucocorticoid therapy strategy The choice of steroid therapy also depends on the clinical manifestation of systemic lupus erythematosus (SLE) and its severity. Mild SLE: For mild cases, involving joint and skin problems or mild fatigue with platelet counts between 50 and 149, doctors may recommend topical treatments or a low dose of oral prednisolone (less than 20 mg daily) for one to two weeks. Moderate SLE: In moderate cases, where inflammation affects organs like the lungs, heart, or kidneys (platelet counts between 25 and 49), the recommended treatment may include oral prednisolone at a dose of less than 0.5 mg per kg of body weight per day. IV methylprednisolone (up to 250 mg) or intramuscular methylprednisolone (80-120 mg) may also be used. Severe SLE: Severe cases, where inflammation causes significant damage to major organs like the heart, lungs, brain, or kidneys (platelet count less than 25), may require a more aggressive approach. Treatment often includes IV methylprednisolone (up to 500 mg for 1-3 doses) or high-dose oral prednisolone (0.75-1 mg per kg per day). Antimalarial therapy: An essential adjunct Hydroxychloroquine an antimalarial medication is often recommended for patients with lupus nephritis unless contraindicated. These drug is beneficial in reducing flare rates, enhancing treatment responses, lowering the risk of cardiovascular and thrombotic events, minimizing organ damage, improving lipid profiles, and preserving bone mass. However, antimalarial drugs are not without side effects, which may include skin rashes, increased skin pigmentation, muscle weakness, and vision changes. Long-term use can increase the risk of retinal damage, so patients need a baseline eye examination and annual check-ups, especially after five years of continuous use. Additional treatment options
Treatment phases The treatment of lupus nephritis is generally divided into three phases:
After successfully completing the maintenance phase, doctors may consider tapering off the medication while closely monitoring for any signs of relapse. Assessing treatment response
Lupus nephritis is a challenging condition requiring a personalized and strategic approach to treatment. Balancing the benefits of potent medications with their potential side effects is essential. By carefully assessing disease severity, selecting appropriate therapies, and monitoring treatment response, healthcare professionals aim to preserve kidney function and improve the quality of life for patients living with this complex disease. |
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