AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Background

Lupus nephritis, one of the most serious manifestations of systemic lupus erythematosus (SLE), usually arises within 5 years of diagnosis; however, renal failure rarely occurs before American College of Rheumatology classification criteria are met.

Histological evidence of lupus nephritis is present in most patients with SLE, even if they do not have clinical manifestations of renal disease. The symptoms are generally related to hypertension, proteinuria, and renal failure. With the advent of more aggressive immunosuppressive and supportive therapy, rates of renal involvement and patient survival are improving.

Pathophysiology

Autoimmunity plays a major role in the pathogenesis of lupus nephritis. The immunologic mechanisms include production of autoantibodies directed against nuclear elements. These autoantibodies form pathogenic immune complexes. In the kidneys, deposition of these immune deposits initiates an inflammatory response by activating the complement cascade and recruiting inflammatory cells that can subsequently be observed on biopsy specimens.

Frequency

United States

The prevalence of SLE is 1 case per 2000 in the general population. Because of the difficulty in diagnosis and a probable underestimation of SLE cases, researchers suggest that the prevalence may be closer to 1 case per 500-1000 population.

Histologically, the kidneys are affected to some degree in most patients with SLE. Estimates of the prevalence of clinical renal involvement in persons with SLE range from 30-90% in published studies. The true prevalence of clinical lupus nephritis is probably around 50%, being more common in certain ethnic groups and in children.

Mortality/Morbidity

• Over the last 4 decades, changes in the treatment of lupus nephritis and general medical care have greatly improved both renal involvement and overall survival. During the 1950s, the 5-year survival rate among patients with lupus nephritis was close to 0%. Recently, with the addition of immunosuppressive agents such as intravenous pulse cyclophosphamide, the 5- and 10-year survival rates are documented as high as 85% and 73%, respectively.
• Morbidity is related to the renal disease itself, as well as to treatment-related complications and comorbidities, including cardiovascular disease and thrombotic events. Progressive renal failure leads to anemia, uremia, and electrolyte and acid-based abnormalities. Hypertension may lead to an increased risk of coronary artery disease and stroke. Nephrotic syndrome may lead to edema, ascites, and hyperlipidemia, which add to the risk of coronary artery disease and the potential for thrombosis.
• Therapy with corticosteroids, cyclophosphamide, and other immunosuppressive agents leads to increased risk of infection. Long-term corticosteroid therapy may lead to osteoporosis, avascular necrosis, diabetes mellitus, and hypertension, among other complications. Cyclophosphamide therapy may cause cytopenias, hemorrhagic cystitis, infertility, and an increased risk of malignancy.

Race

SLE is more common in black people and Hispanic people than in white people. Black people and Asian people may have a higher prevalence of more severe lupus nephritis than other ethnic groups.

Sex

Lupus nephritis is more common in females because the overall prevalence of SLE is higher in females (ie, female-to-male ratio of 9:1); however, males with SLE have an increased prevalence of clinical renal disease with a worse prognosis.

Age

Most patients develop lupus nephritis early in their disease course. SLE is more common among women in the third decade of life, and lupus nephritis occurs in patients aged 20-40 years.

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

History

• General
• • Patients with active lupus nephritis often have other symptoms of active systemic lupus erythematosus (SLE), including fatigue, fever, rash, arthritis, serositis, or CNS disease. These are more common with focal proliferative and diffuse proliferative lupus nephritis.
  • Occasionally, patients are asymptomatic; yet, during regular follow-up, laboratory abnormalities such as elevated serum creatinine levels, low albumin levels, or urinary protein or sediment suggest active lupus nephritis. This is more typical of mesangial or membranous lupus nephritis.
• Nephritis
• • Symptoms related to active nephritis may include peripheral edema secondary to hypertension or hypoalbuminemia. Extreme peripheral edema is more common in persons with diffuse proliferative or membranous lupus nephritis because these renal lesions are commonly associated with heavy proteinuria.
  • Other symptoms directly related to hypertension that are commonly associated with diffuse proliferative lupus nephritis include headache, dizziness, visual disturbances, and signs of cardiac decompensation.

Physical

• Focal proliferative and diffuse proliferative lupus nephritis: The physical examination may reveal evidence of generalized active SLE with the presence of a rash, oral or nasal ulcers, synovitis, or serositis. Signs of active nephritis are also common.
• Active lupus nephritis: Patients have hypertension, peripheral edema, and, occasionally, cardiac decompensation.
• Membranous lupus nephritis: Signs of an isolated nephrotic syndrome are common. These include peripheral edema, ascites, and pleural and pericardial effusions without hypertension.

Causes

• Genetic factors
• • As with many autoimmune disorders, evidence suggests that genetic predisposition plays an important role in the development of both SLE and lupus nephritis. Multiple genes, many of which are not yet identified, mediate this genetic predisposition.
  • SLE is more common in first-degree relatives of patients with SLE (familial prevalence of 10-12%). Concordance rates are higher in monozygotic twins (24-58%) than in dizygotic twins (2-5%), supporting an important role for genetics in the development of SLE. However, the concordance rate in monozygotic twins is not 100%, suggesting that environmental factors trigger development of clinical disease.
• HLA class II genes
• • HLA-DR2 and HLA-DR3 are associated with SLE.
  • HLA-DR4 is associated with a lower prevalence of SLE and appears to be protective.
• Complement genes
• • C1Q, C1R, and C1S deficiencies are associated with SLE, lupus nephritis, and production of anti–double-stranded DNA (anti-dsDNA).
  • C2 and C4 deficiencies are associated with SLE or lupuslike syndrome.
  • C4A and C4B (possibly) gene deletions are associated with SLE.
• FcgR genes
• • These mediate the binding of immunoglobulin G (IgG) and IgG-containing immune complexes to cells such as macrophages and other mononuclear phagocytes.
  • Fcg RIIa binds to IgG₂ and is encoded by 2 codominant alleles, which are H131 (or high affinity) and R131 (or low affinity). The low-affinity phenotype (homozygous for R131 allele; 131R/R) is associated with lupus nephritis among the black population.
  • Fcg RIIIa binds to IgG₁ and is encoded by 2 codominant alleles, which are V158 (or high affinity) and F158 (or low affinity). The low-affinity phenotype (homozygous for F158 allele; 158F/F) is associated with SLE.
• Cytokine genes: Certain polymorphisms of the IL10 gene (high producers) and possibly the IL1RN and TNFA genes (low producers) are associated with SLE.
• Mannose-binding lectin genes: These gene polymorphisms are associated with an increased risk of SLE.
• Apoptosis genes: Defects of several apoptosis genes are associated with lupuslike syndromes in mice and, rarely, SLE in humans, including CD95 (Fas) and CD178 (FasL).
• Immunologic factors
• • The initial autoantibody response appears to be directed against the nucleosome, which arises from apoptotic cells. Patients with SLE have poor clearance mechanisms for the cellular debris. Nuclear debris from apoptotic cells induces interferon-a by plasmacytoid dendritic cells, which are a potent inducer of the immune system and autoimmunity. Autoreactive B lymphocytes, which are normally inactive, become active in SLE because of a malfunction of normal homeostatic mechanisms, resulting in escape from tolerance. This leads to the production of autoantibodies. Other autoantibodies, including anti-dsDNA antibodies, develop through a process of epitope spreading. These autoantibodies develop over time, in an orderly fashion, months to years before the onset of clinical SLE. Lupus nephritis is associated with the production of nephritogenic autoantibodies; their characteristics are as follows:
  • • Antigen specificity directed against nucleosome or dsDNA: Some anti-dsDNA antibodies cross-react with the glomerular basement membrane.
    • Higher-affinity autoantibodies may form intravascular immune complexes, which are deposited in glomeruli.
    • Cationic autoantibodies have a higher affinity for the anionic glomerular basement membrane.
    • Autoantibodies of certain isotypes (IgG₁ and IgG₃) readily activate complement.
  • Immune complexes form intravascularly and are deposited in glomeruli. Alternatively, autoantibodies may bind to antigens already located in the glomerular basement membrane, forming immune complexes in situ. Immune complexes promote an inflammatory response by activating complement and attracting inflammatory cells, including lymphocytes, macrophages, and neutrophils. The histologic type of lupus nephritis that develops depends on a number of factors, including the antigen specificity and other properties of the autoantibodies, and the type of inflammatory response that is determined by other host factors. In more severe forms of lupus nephritis, proliferation of endothelial, mesangial, and epithelial cells and the production of matrix proteins lead to fibrosis.

DIFFERENTIALS

Section 4 of 12  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Other Problems to be Considered

Mesangial glomerulonephritis
Glomerulosclerosis

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Lab Studies

• General
• • Evaluating renal function in patients with systemic lupus erythematosus (SLE) to detect any renal involvement early is important because early detection and treatment can significantly improve renal outcome.
  • Laboratory tests to evaluate renal function include the following:
  • • Blood urea nitrogen testing
    • Serum creatinine level
    • Urinalysis (to check for protein, RBCs, and cellular casts)
    • Spot urine test for creatinine and protein concentration (Normal creatinine excretion is 1000 mg/24 h/1.75 m²; normal protein excretion is 150-200 mg/24 h/1.75 m²; normal urinary protein-to-creatinine ratio is <0.2.)
    • Twenty-four–hour urine test for creatinine clearance and protein excretion
• Tests of SLE disease activity
• • Disease activity can be evaluated with anti-dsDNA, complement determinations (C3, C4, and CH₅₀), and erythrocyte sedimentation rate (ESR) or C-reactive protein. The C-reactive protein level is generally not elevated in patients with SLE, even with active disease, unless the patient has significant arthritis or infection.
  • Generally, an elevated ESR and anti-dsDNA and low C3 and C4 levels are associated with active nephritis, especially focal proliferative and diffuse proliferative lupus nephritis.
  • Clinically relevant lupus nephritis is associated with a 30% decrease in creatinine clearance, proteinuria of greater than 1000 mg/d, and renal biopsy findings indicating active lupus nephritis.
  • Anti-nucleosome antibodies appear early in the course of the autoimmune response in SLE, they have high sensitivity and specificity for a diagnosis of SLE, and the titers correlate with disease activity. Anti-C1q antibodies are associated with lupus nephritis; higher titers correlate with active renal disease.

Procedures

• Renal biopsy
• • Renal biopsy should be considered for any patient with SLE who has clinical or laboratory evidence of active nephritis, especially with the first episode of nephritis.
  • Renal biopsy may be useful in patients with recurrent episodes of nephritis, depending on the clinical circumstances. By revealing the histologic pattern and stage of disease (activity and chronicity), renal biopsy is useful in determining prognosis and treatment.
  • Findings from a thorough clinical and laboratory evaluation can be used to predict the histologic type of lupus nephritis in approximately 70-80% of patients; however, this is not accurate enough considering the toxicity of some of the treatment protocols. A good rule is to perform a renal biopsy if the findings will potentially alter patient management. If a particular patient has other manifestations of SLE (eg, severe CNS or hematologic involvement) and will be treated with cyclophosphamide, a biopsy may not be necessary but should still be considered because it may help predict renal outcome.
  • Sampling error can occur during a renal biopsy. Thus, the results of the biopsy should always be evaluated for consistency with the clinical and laboratory presentation of the patient.
  • The experience of pathologists in reading lupus nephritis biopsy specimens vary considerably. Studies have suggested that the most consistent readers are in larger medical centers with substantial populations of patients with SLE.

Staging

• Pathologic classification
• • The classification of lupus nephritis was revised by the International Society of Pathology/Renal Pathology Society (ISN/RPS) in 2003 and is based on light microscopy, immunofluorescence, and electron microscopy findings from renal biopsy specimens. This is based on earlier classifications by the World Health Organization (WHO) in 1974 and 1982. See Table 1.
  • In addition to the pathologic classification, activity and chronicity indices are scored pathologically and predict the renal prognosis (progression of renal disease). See Table 2.
  • The activity index reflects the state of active inflammation observed at biopsy, which may be reversible with medical therapy.
  • The chronicity index reflects the amount of fibrosis and scarring, which are unlikely to respond to therapy. Renal lesions with a high activity index are more likely to respond to aggressive therapy, whereas renal lesions with high chronicity are not.

    Table 1. International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 Classification of Lupus Nephritis

    Class I Minimal mesangial lupus nephritis	Light microscopy findings	Normal
    	Immunofluorescenceelectron microscopy findings	Mesangial immune deposits
    	Clinical manifestations	Mild proteinuria
    Class II Mesangial proliferative lupus nephritis	Light microscopy findings	Purely mesangial hypercellularity or mesangial matrix expansion with mesangial immune deposits
    	Immunofluorescence electron microscopy findings	Mesangial immune deposits; few immune deposits in subepithelial or subendothelial deposits possible
    	Clinical manifestations	These patients have mild renal disease such as asymptomatic hematuria or proteinuria that usually does not warrant specific therapy.
    Class III Focal lupus nephritis Class III (A) Active lesions: focal proliferative lupus nephritis Class III (A/C) Active and chronic lesions: focal proliferative and sclerosing lupus nephritis Class III (C) Chronic inactive lesions: focal sclerosing lupus nephritis	Light microscopy findings	Active or inactive focal, segmental, or global glomerulonephritis involving <50% of all glomeruli
    	Immunofluorescence electron microscopy findings	Subendothelial and mesangial immune deposits
    	Clinical manifestations	Many patients present with active generalized SLE and mild-to-moderate renal disease with hematuria and moderate proteinuria; significant minority show worsening renal function and may progress to class IV lupus nephritis.
    Class IV Diffuse lupus nephritis Class IV-S (A) Active lesions: Diffuse segmental proliferative lupus nephritis Class IV-G (A) Active lesions: Diffuse global proliferative lupus nephritis Class IV-S (A/C) Active and chronic lesions: diffuse global proliferative and sclerosing lupus nephritis Class IV-S (C) Chronic inactive lesions: diffuse segmental sclerosing lupus nephritis Class IV-G (C) Chronic inactive lesions: Diffuse global sclerosing lupus nephritis	Light microscopy findings	Active or inactive diffuse, segmental or global glomerulonephritis involving >50% of all glomeruli; subdivided into diffuse segmental (class IV-S) when >50% of involved glomeruli have segmental lesions (involving less than half of glomerular tuft) and diffuse global (class IV-G) when >50% of involved glomeruli have global lesions
    	Immunofluorescence electron microscopy findings	Subendothelial immune deposits
    	Clinical manifestations	These patients usually present with clinical evidence of renal disease including hypertension, edema, active urinary sediment, worsening renal function, and nephrotic range proteinuria is present; these patients often have active extrarenal SLE.
    Class V Membranous lupus nephritis	Light microscopy findings	Diffuse thickening of glomerular basement membrane without inflammatory infiltrate; possibly, subepithelial deposits and surrounding basement membrane spikes on special stains, including silver and trichrome; may occur in combination with class II or IV; may show advanced sclerosis
    	Immunofluorescence electron microscopy findings	Subepithelial and intramembranous immune deposits; subendothelial deposits present only when associated proliferative component is present
    	Clinical manifestations	These patients have clinical and laboratory features of nephrotic syndrome, usually without manifestations of active SLE.
    Class VI Advanced sclerosis lupus nephritis	Light microscopy findings	Advanced glomerular sclerosis involving >90% of glomeruli, interstitial fibrosis, and tubular atrophy, all morphological manifestations of irreversible renal injury
    	Clinical manifestations	These patients usually have significant renal insufficiency or end-stage renal disease and are unlikely to respond to medical therapy.

    
    Table 2. Active and Chronic Glomerular Lesions

    Activity Index	Chronicity Index
    • Endocapillary hypercellularity with or without leukocyte infiltration; luminal reduction • Karyorrhexis • Fibrinoid necrosis • Rupture of glomerular basement membrane • Cellular or fibrocellular crescents • Subendothelial deposits on light microscopy • Intraluminal immune aggregates	• Glomerular sclerosis; segmental, global • Fibrous adhesion • Fibrous crescents

  • These indices serve as a prognostic tool and a general guide to therapy. Signs of activity justify aggressive medical therapy because such therapy may arrest or reverse the pathologic changes. Signs of chronicity suggest irreversibility, and aggressive therapy is less likely to affect the outcome. The activity and chronicity indices are evaluated at a single point in time, and renal lesions may transform from one class to another either spontaneously or as a result of treatment.

TREATMENT

Section 6 of 12  

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• Introduction
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• Differentials
• Workup
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• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Medical Care

• General
• • The principal goal of therapy is to normalize renal function or, at least, to prevent the progressive loss of renal function. Therapy differs depending on the pathologic lesion.
  • Strongly consider performing a renal biopsy in patients who present with lupus nephritis.
  • Assess activity and chronicity indices.
  • Treat extrarenal manifestations and other variables that may affect the kidneys.
• Medications
• • Use corticosteroids if the patient has clinically significant renal disease. Use immunosuppressive agents, particularly cyclophosphamide, azathioprine, or mycophenolate mofetil, if the patient has aggressive proliferative renal lesions because they improve the renal outcome. They can also be used if the patient has an inadequate response or excessive sensitivity to corticosteroids.
  • Treat hypertension aggressively. Consider angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) if the patient has significant proteinuria, unless significant renal insufficiency is present.
  • Restrict fat intake or use lipid-lowering therapy such as statins for hyperlipidemia secondary to nephrotic syndrome.
  • Restrict protein intake if renal function is significantly impaired.
  • Administer calcium supplementation to prevent osteoporosis if the patient is on long-term corticosteroid therapy and consider adding a bisphosphonate.
  • Avoid drugs that affect renal function, including nonsteroidal anti-inflammatory drugs, especially in patients with elevated creatinine levels. Nonacetylated salicylates can be used to safely treat inflammatory symptoms in patients with renal disease.
  • Patients should avoid pregnancy if they have active lupus nephritis because it may worsen their renal disease.
  • Patients with end-stage renal disease, sclerosis, and a high chronicity index based on renal biopsy findings are unlikely to respond to aggressive therapy. In these cases, focus therapy on extrarenal manifestations of systemic lupus erythematosus (SLE) and on possible kidney transplantation.
• Therapies for specific types of lupus nephritis based on renal pathology
• • Class I: Minimal mesangial lupus nephritis require no specific therapy.
  • Class II: Mesangial proliferative lupus nephritis may require treatment if proteinuria is greater than 1000 mg/d. Consider prednisone in low-to-moderate doses (ie, 20-40 mg/d) for 1-3 months, with subsequent taper.
  • Classes III and IV: Patients with either focal or diffuse lupus nephritis are at high risk of progressing to end-stage renal disease and require aggressive therapy.
  • • Administer prednisone 1 mg/kg/d for at least 4 weeks, depending on clinical response. Then, taper it gradually to a daily maintenance dose of 5-10 mg/d for approximately 2 years. In acutely ill patients, intravenous methylprednisolone of up to 1000 mg/d for 3 days may be used to initiate corticosteroid therapy.
    • Use immunosuppressive drugs in addition to corticosteroids in patients who do not respond to corticosteroids alone, who have unacceptable toxicity to corticosteroids, who have worsening renal function, who have severe proliferative lesions, or who have evidence of sclerosis on renal biopsy specimens. Both cyclophosphamide and azathioprine are effective for proliferative lupus nephritis, although cyclophosphamide is apparently more effective in preventing progression to end-stage renal disease. Mycophenolate mofetil has been shown to be effective in treating these patients and may be used alone or sequentially after a 6-month course of intravenous cyclophosphamide.
    • Administer intravenous cyclophosphamide monthly for 6 months and every 2-3 months thereafter, depending on clinical response. The usual duration of therapy is 2-2.5 years. Reduce the dose if the creatinine clearance is less than 30 mL/min. Adjust the dose depending on the hematologic response. Gonadotropin-releasing hormone analog, leuprolide acetate, protects against ovarian failure.
    • Azathioprine can also be used as a second-line agent, with dose adjustments depending on hematologic response.
    • Mycophenolate mofetil is useful in patients with focal or diffuse lupus nephritis and has been shown to be at least as effective as intravenous cyclophosphamide with less toxicity in patients with stable renal function.
  • Class V: Patients with membranous 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 proliferative component is present on renal biopsy samples. Some clinical evidence indicates that azathioprine, cyclophosphamide, cyclosporine, and chlorambucil are effective in reducing proteinuria. Mycophenolate mofetil may also be effective.
  • Rituximab, a B-lymphocyte–depleting therapy, appears to be effective in SLE and is being investigated as a treatment for SLE and lupus nephritis. Infliximab, a tumor necrosis factor (TNF)–alpha antagonist, was beneficial in a small series of patients with SLE, including several with lupus nephritis. Abetimus, a B-lymphocyte tolerogen, was not effective in a large controlled trial in preventing flares of lupus nephritis, although it did reduce levels of anti-DNA antibodies.
• End-stage renal disease
• • Patients with end-stage renal disease need dialysis and are good candidates for kidney transplantation.
  • Patients with end-stage renal disease secondary to SLE represent 1.5% of all patients on dialysis in the United States. The survival rate among patients on dialysis is fair (ie, 5-y survival rate of 60-70%) and is comparable with patients on dialysis who do not have SLE.
  • Hemodialysis is preferred over peritoneal dialysis because several studies have documented higher anti-dsDNA levels, more thrombocytopenia, and higher steroid requirements in patients with SLE and end-stage renal disease who are on peritoneal dialysis. Hemodialysis also has anti-inflammatory effects with decreased T-helper lymphocyte levels. SLE is generally quiescent in patients on hemodialysis, although flares, including rash, arthritis, serositis, fever, and leukopenia, may occur and require specific treatment.

Surgical Care

• Patients with SLE account for 3% of all renal transplantations in the United States.
• Ensure that the patient does not have active SLE disease at the time of transplantation.
• A 3-month period of dialysis is usually prudent to prevent spontaneous renal recovery.
• Substantial evidence shows that patients with SLE fare worse than patients without SLE in terms of graft survival. Living-related allografts show better outcomes than cadaveric allografts.
• In patients with SLE, reasons for a more severe outcome after transplantation include recurrent lupus nephritis and concomitant antiphospholipid antibody syndrome resulting in allograft loss.

Consultations

• Nephrologist (for renal biopsy or, if desired, for help in management of renal disease)
• Pathologist (for renal biopsy): The experience of pathologists in reading lupus nephritis biopsy specimens varies considerably. The most consistent readers are usually found in larger academic centers with substantial populations of patients with SLE.

Diet

Alter the diet according to the presence of hypertension, hyperlipidemia, and renal insufficiency.

MEDICATION

Section 7 of 12  

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• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Corticosteroids are used in all patients with clinically significant renal disease. Immunosuppressive agents, particularly cyclophosphamide, azathioprine, and mycophenolate mofetil, are used in patients with aggressive renal lesions because they improve the renal outcome. They may also be used in patients with inadequate response or excessive toxicity to corticosteroids. Cyclosporine has been used occasionally.

Drug Category: Corticosteroids

These agents are very useful in controlling acute inflammatory manifestations of systemic lupus erythematosus (SLE). Corticosteroids alone may be adequate to treat milder forms of lupus nephritis with a lower risk of progressive renal dysfunction, such as minimal mesangial lupus nephritis, mesangial proliferative lupus nephritis, early focal lupus nephritis, or membranous lupus nephritis. Oral corticosteroids can be used in most patients. If adequate absorption is a concern (eg, bowel edema in a patient with nephrosis), intravenous methylprednisolone can be used.

Drug Category: Immunosuppressives

In particular, cyclophosphamide and azathioprine are used in patients with aggressive renal lesions (eg, focal lupus nephritis, diffuse lupus nephritis) because they improve renal outcome. These agents can also be used in patients with inadequate response or excessive toxicity to corticosteroids. In some studies, mycophenolate mofetil has been shown to be effective for treatment of lupus nephritis.

FOLLOW-UP

Section 8 of 12  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Further Outpatient Care

• Follow-up visits
• • Schedule the patient for close follow-up after the initiation of therapy, especially those with focal lupus nephritis, diffuse lupus nephritis, or membranous lupus nephritis, to monitor therapy response and treatment-related toxicities.
  • Upon the initiation of high-dose corticosteroids, cyclophosphamide, azathioprine, or mycophenolate mofetil, arrange for the patient to visit a physician at least every month.
• Follow-up testing
• • Use the ESR, anti-dsDNA, and C3 and C4 to monitor systemic lupus erythematosus (SLE) disease activity.
  • Cyclophosphamide therapy requires regular laboratory monitoring, including CBC count and urinalysis.
  • Azathioprine and mycophenolate mofetil therapy requires regular monitoring of CBC count and less frequent monitoring of liver function test results.
• Determine renal function, urinalysis results, and albumin levels monthly and check spot urine for creatinine and protein or determine creatinine clearance and 24-hour urinary protein excretion every 3 months. After the initiation of therapy and as the patient's condition stabilizes, monitoring may be less frequent.
• Exercise vigilance with flares of lupus nephritis, even in patients who are stable for many months or years.

Complications

• Disease-related complications may be secondary to hypertension and nephrotic syndrome and include the following:
• • Cardiovascular complications
  • Stroke
  • Hyperlipidemia
  • Hypercoagulability with thrombosis
• Treatment-related complications include the following:
• • Infections
  • Cytopenias
  • Bladder toxicity
  • Infertility
  • Premature gonadal failure
  • Osteoporosis
  • Avascular necrosis
  • Premature atherosclerosis
  • Small increased risk of malignancy

Prognosis

• Poor prognostic indicators
• • Delay in treatment of more than 5 months from onset of nephritis
  • Young age at onset of nephritis
  • Male sex
  • Black racial background
  • Hypertension
  • Nephrotic syndrome
  • Elevated creatinine level (>3 mg/dL) at presentation
  • Persistently elevated anti-dsDNA and low C3 and C4 levels
  • Renal biopsy findings showing diffuse lupus nephritis or high chronicity index
• Excellent prognosis: Minimal mesangial lupus nephritis and mesangial proliferative lupus nephritis (ISN/RPS 2003 classes I and II) carry an excellent prognosis.
• Good prognosis: Focal lupus nephritis (ISN/RPS 2003 class III) carries a good prognosis, with only a minority of patients developing progressive renal failure.
• Fair prognosis
• • Diffuse lupus nephritis (ISN/RPS 2003 class IV) carries a fair prognosis, with a significant number of patients developing progressive renal failure.
  • Membranous lupus nephritis (ISN/RPS 2003 class V) carries a fair prognosis, with a significant number of patients developing progressive renal deterioration gradually over time.
• Poor prognosis: Advanced sclerosis lupus nephritis (ISN/RPS 2003 class VI) carries a poor prognosis.

Patient Education

• Educate the patient about the serious nature of lupus nephritis, various therapies, and potential toxicities of treatment.
• The patient must understand signs of treatment-related toxicities, such as infection and bladder toxicity, so an immediate evaluation can be initiated.
• These patients must also understand the risks for atherosclerotic and thrombotic events, even in young women, and that any signs or symptoms that suggest such an event warrant an immediate evaluation.
• For excellent patient education resources, visit eMedicine's Diabetes Center, Blood and Lymphatic System Center, and Arthritis Center. Also, see eMedicine's patient education articles Chronic Kidney Disease and Lupus (Systemic Lupus Erythematosus).

MISCELLANEOUS

Section 9 of 12  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Medical/Legal Pitfalls

• Before instituting therapy for lupus nephritis, performing a renal biopsy is generally recommended to confirm the diagnosis and to determine the type of histology as a guide to appropriate therapy. The risk of renal biopsy must be clearly explained. If the patient refuses renal biopsy, the patient must understand how this can limit diagnostic accuracy.
• Because the therapy for lupus nephritis has significant potential for toxicity, the potential adverse effects of corticosteroids and immunosuppressive agents must be discussed. The risks of withholding therapy must also be discussed.

Special Concerns

• Pediatric lupus nephritis
• • Renal manifestations are more common in pediatric patients with systemic lupus erythematosus (SLE) than in adults with SLE. Renal biopsy findings associated with pediatric lupus nephritis show a higher rate of focal and diffuse lupus nephritis compared with findings associated with adult lupus nephritis, and the prevalence of progression to renal failure is increased. Renal involvement occurs in two thirds of children and adolescents with SLE. Since the advent of immunosuppressive therapy, survival rates have improved; however, this improvement has occurred at the expense of long-term morbidity and complications of therapy, with profound consequences.
  • In the treatment of patients with pediatric lupus nephritis, early therapy to control the disease should be balanced with long-term follow-up to minimize the adverse effects of therapy and the disease complications. Poor prognostic features include a renal biopsy specimen that shows diffuse lupus nephritis, persistent hypertension, persistent elevated anti-dsDNA, and hypocomplementemia.
• Pregnancy and lupus nephritis
• • Patients should avoid pregnancy because it may aggravate renal disease, especially in the presence of active lupus nephritis, nephrotic syndrome, severe hypertension, or serum creatinine levels elevated to more than 2 mg/dL.
  • Patients with lupus nephritis have a 50-60% chance of renal flare during pregnancy if they conceive during active disease.
  • Patients with well-controlled SLE who conceive after a 3- to 6-month period of remission have a 7-10% chance of renal flare.
  • Pregnant patients with lupus nephritis are prone to preeclampsia. Preexisting hypertension and antiphospholipid antibody syndrome are the 2 most common predisposing factors to preeclampsia.
  • Severe flares during pregnancy may cause acute renal failure and maternal and fetal death. Closely monitor pregnant patients with SLE, aggressively treat exacerbations, and carefully avoid administering teratogenic drugs.

FURTHER READING

Section 10 of 12  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

For more information, see Medscape's Lupus Resource Center.

MULTIMEDIA

Section 11 of 12  

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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Media file 1:  Mesangial proliferative lupus nephritis with moderate mesangial hypercellularity. International Society of Pathology/Renal Pathology Society (ISN/RPS) 2003 class II (hematoxylin and eosin stain; 200X magnification).
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Media file 2:  Focal lupus nephritis. International Society of Pathology/Renal Pathology Society (ISN/RPS) 2003 class III (hematoxylin and eosin stain; 100X magnification).
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Media file 3:  Focal lupus nephritis, immunofluorescence. International Society of Pathology/Renal Pathology Society (ISN/RPS) 2003 class III (200X magnification).
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Media file 4:  Diffuse lupus nephritis with hypertensive vascular changes. International Society of Pathology/Renal Pathology Society (ISN/RPS) 2003 class IV (hematoxylin and eosin stain; 200X magnification).
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Media file 5:  Diffuse lupus nephritis with early crescent formation. International Society of Pathology/Renal Pathology Society (ISN/RPS) 2003 class IV (hematoxylin and eosin stain; 200X magnification).
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Media file 6:  Diffuse lupus nephritis with extensive crescent formation (rapidly progressive glomerulonephritis). International Society of Pathology/Renal Pathology Society (ISN/RPS) 2003 class IV (hematoxylin and eosin stain; 200X magnification).
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Media file 7:  Membranous lupus nephritis. International Society of Pathology/Renal Pathology Society (ISN/RPS) 2003 class V (hematoxylin and eosin stain; 200X magnification).
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Media file 8:  Membranous lupus nephritis showing thickened glomerular basement membrane. International Society of Pathology/Renal Pathology Society (ISN/RPS) 2003 class V (silver stain; 200X magnification).
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Media file 9:  Advanced sclerosis lupus nephritis. International Society of Pathology/Renal Pathology Society (ISN/RPS) 2003 class VI (hematoxylin and eosin stain; 100X magnification).
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REFERENCES

Section 12 of 12

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

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Article Last Updated: Feb 14, 2008