Signs and Symptoms
Presenting features of LN are nonspecific to acute glomerulonephritis, nephrotic syndrome, or both (Table 12.2
). LN is a common cause of inflammatory kidney
disease caused by systemic disease. The kidney involvement may be the presenting feature of SLE in 50% to 70% of patients with LN.17
Some patients report a long history of somatic complaints, and it can take several months or years before the diagnosis is established. The European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) classification system has been used to define SLE for research purposes and has been well validated in both adults20
TABLE 12.2 Presenting Features of Lupus Nephritis
Hematuria (microscopic or gross)
Urinary casts (red blood cell, granular, hyaline)
Proteinuria (albuminuria ± nephrotic syndrome)
Serositis (pleuritis, pericarditis)
Seizures, stroke, headache
Acute kidney injury
Cytopenias (hemolytic anemia, leukopenia, thrombocytopenia)
Chronic kidney disease
Hypergammaglobulinemia/elevated erythrocyte sedimentation rate
The criteria include a positive antinuclear antibody (ANA) at least once as an obligatory entry criterion; followed by additive weighted criteria grouped in seven clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, kidney) and three immunologic (antiphospholipid antibodies [aPLs], complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating 10 points or more are classified as having SLE.
Mucocutaneous manifestations are common in SLE. The malar rash is often associated with exposure to ultraviolet light and can resolve spontaneously. Patients should be asked about photosensitivity. The discoid rash is scarring and can involve the scalp or face. Both oral and nasal ulcers can be present. Livedo reticularis or vasculitis lesions on distal extremities should raise a high index of suspicion. Arthritis can involve several joints and migrate between joints. Fevers, fatigue, and weight loss can be significant.
Urinalysis is mandatory at baseline and periodically to examine for proteinuria, hematuria, and cellular casts, whereas urine protein:creatinine ratios (UPCR), whether spot or 24-hour collection, are required for monitoring response to LN treatment. A routine urinalysis (“dipstick”) can be insufficient to adequately evaluate the presence and source of hematuria in women with SLE. A microscopic examination of the urine sediment, as well as repeat testing in mid-cycle, may be necessary to distinguish glomerular hematuria from urogenital contamination in
women of childbearing age. The urine microscopic analysis is critical to confirm that the hematuria is caused by erythrocyturia and not hemolytic anemia. Spun urine samples can be assessed after a 5-minute centrifugation step at 300× gravity to pellet urinary cells, crystals, and casts. LN can be defined clinically by the presence of proteinuria and glomerular hematuria (dysmorphic red blood cells or red cell casts).
Laboratory evaluation of SLE should also include blood testing for determination of acute-phase reactants, complete blood count (CBC), and biochemical profile. Erythrocyte sedimentation rate (ESR) and C-reactive protein are indirect parameters of inflammation and can be useful in differentiating lupus flare from infection. Hypergammaglobulinemia is a common cause of elevated ESR in SLE, but monitoring Ig levels is only necessary when assessing infection risk from hypogammaglobulinemia during prolonged treatment with B-cell depleting agents.22
CBC with platelet count and differential is requested to check for potential cytopenias. The presence of anemia must be further evaluated with peripheral smear, reticulocyte count, iron studies, and Coombs test. A chemistry panel will evaluate electrolytes, transaminases, and kidney function. Patients should be evaluated for risk factors for atherosclerosis with fasting blood glucose and lipid profile. Depending on the presence of thyroid or liver abnormalities, thyroid function tests, liver function tests, and bilirubin levels are determined or biopsies performed.
Testing for ANA has a low false-negative rate, but it is nonspecific. An extractable nuclear antigen panel or ANA profile can provide data on specificity of ANA and help confirm an SLE diagnosis. Antibodies against RNPs are nonspecific and more common in patients with SLE with an overlap syndrome including features of mixed connective tissue disease. Antibodies against the Smith antigen are more specific to SLE. Other subsets of ANA include anti-chromatin, antihistone, anti-RNA, and anti-DNA antibodies. Antihistone antibodies are present in many patients with drug-induced lupus, up to 75% associated with hydralazine and procainamide,24
but are less commonly seen in SLE.
Anti-double-stranded DNA (dsDNA) antibody titers loosely correlate with LN activity.25
Commercial anti-dsDNA assays detect antibodies with a wide spectrum of fine molecular specificities, including those produced transiently in the context of infections and those that are persistent in the context of true autoimmunity. Some anti-dsDNA antibodies also bind chromatin (DNA epitope accessible), but others are specific to DNA structures that are embedded in chromatin and inaccessible unless DNA is unbound. Confirming the diagnosis of SLE in both children and adults requires further antibody testing. Anti-dsDNA antibodies are specific to SLE, associated with a homogeneous or peripheral ANA pattern, and predict active LN. Anti-Smith antibodies are associated with a speckled ANA pattern.
Low serum levels of complement components C3 and C4 help in the diagnosis; however, normal complement levels do not exclude LN.26
The most important serologic tests are those that detect antibody and complement levels. Complement levels have been used as markers of lupus disease activity; hypocomplementemia often signifies active SLE, especially LN. Because homozygous deficiencies of classical pathway components, such as C1q and C4, can be associated with an increased risk of SLE, it may be difficult to know whether the low complement is due to consumption or from inherited deficiencies of one or more alleles.
Although anti-C1q antibodies are more specific to proliferative classes of LN,27
they can also be detected in hypocomplementemic urticarial vasculitis. To avoid nonspecific binding to any circulating immune complex in SLE samples, diagnostic assays developed for the detection of anti-C1q antibodies require high ionic strength conditions or a solid-phase assay using only the C1q collagen-like region. No commercial assay has yet been approved by regulatory agencies because of insufficient prospective data and unknown inter-test variability. However, in research settings, anti-C1q titers correlate strongly with global disease activity scores in patients with kidney involvement, and higher titers seem to precede kidney flares. Moreover, younger individuals with SLE are more likely to be anti-C1q positive than are older individuals.
aPLs are detected in about 30% of children with SLE and in 40% of adults with SLE.28
The most important aPLs are anticardiolipin and β-2-glycoprotein I antibodies. There are three distinct isoforms of anticardiolipin and beta-2-glycoprotein I antibodies, IgG, IgA, and IgM, with IgG being the most important clinically. However, many other autoantibodies can contribute, so screening tests should also include an assessment for lupus anticoagulant. The presence of lupus anticoagulant causes a prolongation of activated partial thromboplastin time (which is counterintuitive). About 40% of patients with SLE with persistently positive aPLs will develop antiphospholipid syndrome (APS). APS is characterized by recurrent arterial or venous thrombotic events or pregnancy complications (recurrent pregnancy loss, preterm birth, preeclampsia, placental failure, and preterm premature rupture of membranes; see also Chapter 20
). Trauma, surgical procedures, and infections transiently cause aPL positivity.
Although kidney imaging is not necessary for a diagnosis of LN, patients often receive a kidney ultrasound before a kidney biopsy to avoid diagnosing unexpected incidental anatomic abnormalities (eg, hydronephrosis, cysts, or solitary kidney) at the time of a kidney biopsy. In children, the high degrees of inflammation and interstitial edema often seen in LN will manifest as enlargement of both kidneys and increased echogenicity.29
Patients with LN may require further imaging to evaluate for extrarenal manifestations of SLE. These include chest radiographs that will detect cardiomegaly, active pulmonary infiltrates, and serositis. Full workup for cardiopulmonary complications entails doing pulmonary function testing with lung diffusion testing, two-dimensional echocardiography, and high-resolution computed tomography (CT) scans.31
Other imaging modalities include magnetic resonance (MR) imaging of the brain for evaluation of neuropsychiatric lupus or of joints in cases of avascular necrosis. MR or CT angiography will assess for thrombi for lupus-related APS.
The diagnosis of LN is often clinical, and the value of kidney biopsy is in confirmation of the diagnosis, classification for guiding therapy, and scoring of activity and chronicity that provide prognostic information. LN can be seen in isolation but is more typically seen in patients with systemic or extrarenal manifestations of autoimmunity. Hypocomplementemia can distinguish LN from other secondary causes, such as ANCA vasculitis. However, ANCA can be positive along with ANA in patients with LN, and levels of complement components C3 and C4 can be normal in LN. Chronic infections, indwelling shunts, cryoglobulinemia, and
malnutrition can all cause systemic disease that includes hypocomplementemia and nephritis. Full-house immunofluorescence and/or endothelial tubuloreticular inclusions can be seen on kidney biopsy in 70%32
and 45% to 80%.32
of LN cases, respectively, and both together can favor a diagnosis of LN.
Kidney biopsies consistent with LN can be seen in patients with a negative ANA test (which can be found positive on repeat testing). The EULAR/ACR classification system requires a positive ANA test for a diagnosis of SLE and LN.20
Accordingly, true ANA negative patients with immune complex glomerulonephritis and even full-house immunofluorescence should not be diagnosed with LN. However, patients with lupus-like kidney diseases may be evolving toward an eventual diagnosis of SLE. For this reason, many rheumatologists refer to patients as having incomplete lupus or evolving lupus until they meet classification criteria.