Lupus Nephritis (Including Antiphospholipid Antibody Syndrome)
Dawn J. Caster
Scott E. Wenderfer
INTRODUCTION AND GENERAL CONSIDERATIONS
Lupus nephritis (LN) is a common cause of glomerular disease. The prevalence of systemic lupus erythematosus (SLE) is 70 to 90 per 100,000 individuals.1 Although primarily a disease in women of childbearing age, about 15% of affected patients are diagnosed before 18 years and another 15% diagnosed after the age of 65 years. The prevalence of SLE is approximately 2-fold higher in Asians and Hispanics and up to 4-fold higher in Blacks of African descent. In the United States, American Indian/Alaska Native had the highest race-specific SLE estimates for females (271/100,000) and males (54/100,000).1 In Germany, the overall estimated incidence of SLE was 2/100,000 person-years in women and 1/100,000 person-years in men.2 The age-specific incidences of SLE also differed significantly between women and men. In women, the highest incidence of SLE was in the 20- to 25-year-olds (4/100,000 person-years), with a second, lower peak in incidence at menopause. In men, the peak incidence of SLE was in 65- to 70-year-olds (2/100,000 person-years).2
Polymorphisms for over 60 genes have been identified as risk alleles for developing SLE,3 but so far, these still only explain 20% of disease heritability. Genetic polymorphisms are more common in childhood-onset SLE.4 These genes encode components of the immune system, DNA repair pathways, and clearance mechanisms for apoptotic debris. The missing heritability likely comes from complex interactions between genes and environment (eg, ultraviolet light, heavy metals, viral infections) and disrupted epigenetic regulation of gene expression.5
Between 25% and 30% of patients with SLE develop LN.6 The presence of nephritis typically requires escalation and prolongation of therapy. The risk of kidney failure in untreated LN was historically around 50%. With immunomodulatory therapy and corticosteroids, the 10-year risk of kidney failure is now closer to 10%. This risk is higher with delays in diagnosis or treatment initiation, with relapsing disease, and refractory disease. Therefore, early diagnosis and referral to specialty centers are paramount.
PATHOGENESIS
Systemic autoimmunity in SLE begins with loss of tolerance to intracellular self-antigens (chromatin, nucleosomes, DNA, RNA, ribonuclear proteins [RNPs]). Defects in the classical pathway of complement (such as C1q deficiency), DNase
enzymes, and phagocyte receptors contribute to autoantibody generation. Type-I interferon and nuclear factor κ-B pathways, neutrophil extracellular traps, and perturbations in B-cell signaling and B-cell cytokines (such as B-cell activating factor [BAFF]) predispose to LN development. Ultimately, immune complexes form and localize to glomeruli, driving proliferation of resident kidney cells and inflammation by macrophage, dendritic cells, basophils, and B and T lymphocytes.7,8,9,10,11
enzymes, and phagocyte receptors contribute to autoantibody generation. Type-I interferon and nuclear factor κ-B pathways, neutrophil extracellular traps, and perturbations in B-cell signaling and B-cell cytokines (such as B-cell activating factor [BAFF]) predispose to LN development. Ultimately, immune complexes form and localize to glomeruli, driving proliferation of resident kidney cells and inflammation by macrophage, dendritic cells, basophils, and B and T lymphocytes.7,8,9,10,11
Histopathology
Kidney biopsy remains the gold standard for diagnosis. Immunofluorescent antibody staining of glomeruli is typically positive for C1q, C3, immunoglobulin (Ig) A, IgG, and IgM (“full-house” pattern). Kidney injury is classified by the International Society of Nephrology/Renal Pathology Society (ISN/RPS) (Table 12.1).12 The relative frequency of each LN class is similar in children and adults. The utility of distinguishing nonproliferative from proliferative classes (Figure 12.1) is supported by clinical trials in adults and observational studies in pediatrics. The revised 2018 ISN/RPS classification includes scoring for both disease activity and chronicity. High-activity scores suggest higher degrees of inflammation and glomerular hypercellularity, warranting more intense treatment regimens. High-chronicity scores suggest more damage and fibrosis that will not respond well to immunomodulation.
TABLE 12.1 Classification of Lupus Nephritis by the International Society of Nephrology/Renal Pathology Society | |||||||
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 FIGURE 12.1: Histopathology of lupus nephritis: normal capillary with intact podocyte foot processes and no electron-dense deposits. ISN/RPS class I lupus nephritis with minimal mesangial deposits, focal foot process effacement, and no mesangial hypercellularity. ISN/RPS class II lupus nephritis with substantial mesangial deposits, mesangial hyperplasia, and more extensive foot process effacement. ISN/RPS focal (class III) lupus nephritis with scanty subendothelial deposits, mesangial hyperplasia, endocapillary leukocytes, and extensive foot process effacement. ISN/RPS diffuse (class IV) lupus nephritis with numerous subendothelial and a few subepithelial deposits, mesangial hyperplasia, endocapillary leukocytes, and extensive foot process effacement. ISN/RPS membranous (class V) lupus nephritis with numerous subepithelial and a few subendothelial and mesangial deposits and extensive foot process effacement. ISN/RPS, International Society of Nephrology/Renal Pathology Society. (Reproduced with permission from Jennette JC, D’Agati VD, Olson JL, Silva FG. Heptinstall’s Pathology of the Kidney. 7th ed. Wolters Kluwer; 2014: Figure 14.1.) |
Although immune complexes contribute to most cases of LN, occasionally other, nonclassifiable histopathology is encountered. Lupus vasculitis is a pauci-immune, necrotizing glomerulonephritis, often segmental with crescents, which behaves more like antineutrophil cytoplasmic antibody (ANCA) vasculitis than like immune complex nephritis.13 Thrombotic microangiopathy (TMA) can be diagnosed as intraglomerular fibrin staining in association with thrombocytopenia and microangiopathic hemolytic anemia.14 Renal TMA is often associated with antiphospholipid syndrome.15 Lupus podocytopathy presents as isolated proteinuria and diffuse podocyte foot process effacement, with minimal change, mesangial, or focal segmental glomerulosclerosis-like histopathology, without significant electron-dense deposits.16 These forms of lupus kidney involvement have not been studied in clinical trials and often require alternative therapies.
CLINICAL FINDINGS
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.17,18,19 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 and children.21
disease caused by systemic disease. The kidney involvement may be the presenting feature of SLE in 50% to 70% of patients with LN.17,18,19 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 and children.21
TABLE 12.2 Presenting Features of Lupus Nephritis | ||||||||||||||||||
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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.
Laboratory Findings
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).
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.22,23 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.
Special Tests
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.
Imaging Studies
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.29,30
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.
Differential Diagnosis
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%.32,33 of LN cases, respectively, and both together can favor a diagnosis of LN.
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%.32,33 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.
COMPLICATIONS
LN leads to substantial morbidity and is associated with multiple complications including chronic kidney disease (CKD), end-stage kidney disease (ESKD), cardiovascular disease, and increased mortality. Although treatment has improved outcomes, the risk of ESKD is still high, with 10% to 30% of patients developing ESKD 10 years after initial diagnosis.34 SLE alone is associated with an increased risk of cardiovascular disease, but LN is associated with a 9-fold greater risk of atherosclerotic cardiovascular disease compared to patients having SLE without nephritis.35,36 Patients with LN have an approximately 6-fold increase in mortality when compared to the general population, and patients who develop ESKD have the highest mortality rate, with greater than 20-fold increase compared to the general population.37,38,39 The leading causes of death in patients with LN include infection and cardiovascular and kidney diseases. LN treatment, which primarily consists of corticosteroids and immunosuppressive agents, carries additional complications including infections, bone disease, infertility (with the use of cyclophosphamide), malignancy, and metabolic and cardiovascular disease.40
RISK FACTORS/PREDISPOSITIONS
SLE is most prevalent in women of childbearing age, with a female-to-male ratio of approximately 9:1. Most patients with SLE who develop LN will do so within 5 years of initial SLE diagnosis.41 Depending on the population, 25% to 50% of patients with SLE will have evidence of kidney involvement at initial presentation.41 Factors that increase the risk of LN include African, Hispanic, or Asian ancestry; childhood-onset disease; and male sex.41,42,43
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