1. How common is systemic lupus erythematosus (SLE), and how often is lupus nephritis present in patients with this disease?

The prevalence of SLE in the United States is around 40/100,000 (0.04%); it has a peak age of onset of 20 to 40 years and is more common in women and certain ethnic groups (especially African Americans). Kidney involvement occurs in 40% of patients with SLE, and the kidney is the most common major organ affected.

2. What is the single most important test to order to determine if a patient with SLE needs further evaluation for lupus nephritis?

A urinalysis should be performed at every visit in patients with SLE, because lupus nephritis may be asymptomatic or intermittent. The presence of protein or blood on dipstick and/or the presence of red blood cells (RBCs) or RBC casts on microscopic examination requires further workup for lupus nephritis. Glycosuria (with a normal plasma glucose) and sterile pyuria can also represent kidney involvement. Proteinuria, if present on dipstick, should be quantified. The presence of any blood, protein, or casts in the urine warrants further nephrologic evaluation.

3. How does a patient with lupus nephritis present clinically?

Although kidney involvement may be the first sign of SLE in an individual patient, lupus nephritis typically becomes clinically apparent as a manifestation of the systemic disease. In the Systemic Lupus International Collaborating Clinics classification criteria, patients with biopsy-proven lupus nephritis in the presence of antinuclear antibodies (ANA) or antibodies to double-stranded DNA (anti-dsDNA) satisfy criteria for a diagnosis of SLE. Some patients with lupus nephritis are asymptomatic, but classically patients will have a variety of systemic manifestations including but not limited to the following:

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  Cutaneous abnormalities

  
  
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  Fever

  
  
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  Malaise

  
  
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  Weight loss

  
  
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  Synovitis

  
  
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  Raynaud phenomenon

  
  
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  Serositis

  
  
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  Pericarditis

  
  
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  Retinopathy

  
  
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  Thrombotic microangiopathy (TMA)

  
  
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  Neuropsychiatric involvement

  
  
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  Hematologic abnormalities

  
  
  
  
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    Leukopenia

    
    
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    Anemia

    
    
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    Thrombocytopenia

  
  

Evidence of immunologic activity in the serum is usually present as ANA, anti-dsDNA and Smith (anti-Sm), and hypocomplementemia (see Serologic Evaluation, further on). The pattern of clinical activity varies between patients but characteristically is one of relapsing and remitting disease. Only 10% of patients with discoid lupus will develop SLE; if so, they seldom develop nephritis. Certain medications, such as hydralazine or procainamide, may cause drug-induced systemic lupus, but they are only rarely associated with lupus nephritis.

In patients with kidney involvement, presentation can range from subtle disease such as asymptomatic microscopic hematuria and proteinuria on urinalysis with normal kidney function to nephritic and/or nephrotic syndrome and rapidly progressive glomerulonephritis with kidney failure and hypertension. Nephrotic syndrome is present in approximately 25% of patients during their disease course. Microscopic hematuria is commonly associated with proteinuria and rarely found in isolation. Kidney failure, defined by an elevated serum creatinine, is present in approximately 40% of patients with lupus nephritis.

4. If my patient with lupus has hematuria or proteinuria, what immunologic serology should I order to determine if lupus nephritis is present or active?

The only definitive way to determine if lupus nephritis is present or active is to perform a kidney biopsy. However, certain types of immunologic serology are useful to establish parameters of activity that can be helpful to diagnose SLE and/or monitor relapses or response to treatment. Serologic evaluation should include

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  ANA

  
  
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  anti-Smith (anti-Sm)

  
  
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  anti-Sjögren Syndrome A antigen (anti-Ro/SSA)

  
  
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  anti-Sjögren Syndrome B antigen (anti-La/SSB)

  
  
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  antiribonucleoprotein

  
  
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  anti-dsDNA

  
  
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  Complement components

  
  
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  Rheumatoid factor

  
  
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  Antiphospholipid antibodies

This serology may be positive in a variety of diseases other than SLE, but anti-Sm is quite specific for SLE. Anti-dsDNA antibodies, when present, are strongly associated with lupus nephritis. Hypocomplementemia and anti-dsDNA antibodies will typically correlate with disease activity.

5. When does a kidney biopsy need to be performed in the setting of SLE?

Any patient suspected of having lupus nephritis should be further evaluated with a kidney biopsy. This procedure is considered when abnormalities—such as protein, blood, or casts—are present on urinalysis, often coupled with abnormal serology or reduced kidney function. Severe involvement, such as nephrotic syndrome or nephritic syndrome with or without kidney failure, will require a kidney biopsy for further evaluation. Even when subtle abnormalities are present clinically (i.e., normal kidney function with or without hematuria and less than 1 g of proteinuria/day), severe lupus nephritis may be present on kidney biopsy. Thus a kidney biopsy should be performed to establish a diagnosis, determine prognosis, and guide therapy. Many patients may require more than one biopsy during their disease course. This procedure may be necessary to alter therapy, because the characteristics of lupus nephritis may change over time or to determine if there is late progression of the disease, which may not be amenable to further immunosuppressive treatment.

6. What are the pathologic features of lupus nephritis?

The Renal Pathology Society/International Society of Nephrology (RPS/ISN) classification system divides kidney biopsies into six groups based on pathologic features in the glomeruli ( Table 32.1 ). The number of active and/or chronic (or inactive) lesions guides treatment and is important in determining the patient’s long-term kidney prognosis. Common active and chronic lesions in patients with lupus nephritis are listed in Box 32.1 . Immunofluorescence is characterized by the presence of glomerular deposits of immune reactants that stain for IgG (dominantly), IgA, IgM, C3, and C1q (known as the “full house” pattern). Electron-dense deposits representing immune complexes are seen on electron microscopy in the mesangium and are found in the subepithelial and/or subendothelial locations. The presence of tubuloreticular inclusions in the glomerular capillary endothelial cell on electron microscopy is relatively specific for lupus nephritis.

7. Does the lupus nephritis classification provide information on treatment, pathogenesis, and/or prognosis?

The RPS/ISN classification provides valuable information on how to treat patients with lupus nephritis. Treatment of severe lupus requires aggressive immunomodulatory therapy. Severe lupus encompasses classes III, IV, and V (if it has concomitant features of III and IV). Pure mesangial (II) or pure membranous (V) lupus typically require less aggressive immunomodulatory therapy. Class III and class IV disease are further subdivided based on the inflammatory activity or chronicity of the lesions on kidney biopsy. The World Health Organization (WHO) classification was commonly used prior to the RPS/ISN classification. The advantage of the WHO classification is that it categorized information about the pathogenesis of the lesions (i.e., immune complex–mediated or non-immune complex–mediated). The WHO classification also helps delineate prognosis, because patients with severe lupus nephritis have a worse prognosis than those with less severe disease. In addition, those with diffuse proliferative lesions are generally more likely to achieve a remission and less likely to progress to end-stage kidney failure than those with severe segmental lesions, but both have a much higher risk of progression compared with mesangial or pure membranous disease.

8. What nephropathology occurs in patients with SLE that is not part of the classic lupus nephritis?

Although glomerular inflammatory involvement is the prototypical example of lupus nephritis, the tubules, interstitium, and vasculature of the kidney can also be affected.

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  Tubulointerstitial disease: proximal tubular dysfunction and hyperkalemic renal tubular acidosis can be seen in patients with lupus. Acute interstitial nephritis including active tubulitis (infiltration and invasion of the tubules) can be seen with or without glomerular disease.

  
  
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  Podocytopathy: the epithelial cells in the glomerular capillaries may become effaced, termed podocytopathy , which typically gives rise to the dramatic onset of the nephrotic syndrome, similar to the clinical presentation of minimal change disease.

  
  
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  Antiphospholipid syndrome (APS): antiphospholipid antibodies (aPL) can be seen in up to 40% of SLE patients, and about 50% of these patients can develop APS. APS is characterized by a combination of arterial and/or venous thrombosis in the setting of positive aPL. Thus patients are at risk for renal artery stenosis and thrombosis, renal vein thrombosis, and renal infarction. Antiphospholipid nephropathy (APSN) refers to the vascular lesions in glomeruli, small arteries, arterioles, and interlobular arteries seen in patients with persistent aPL (with or without APS). TMA is the distinct histologic finding in acute lesions. Chronic vascular lesions include arterial fibrous intimal hyperplasia, arteriosclerosis, and organized thromboses. Kidney manifestations of APS can occur in the presence or absence of lupus nephritis, and APSN can be associated with all classes of lupus nephritis.

  
  
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  Acute tubular necrosis and interstitial nephritis can be seen in patients taking nonsteroidal anti-inflammatory agents for arthritis.