Renal disease in systemic lupus erythematosus with emphasis on classification of lupus glomerulonephritis: advances and implications.
* Context.--Systemic lupus erythematosus is an autoimmune disease
with protean clinical and pathologic manifestations involving almost all
organs in the body. There is a high incidence of renal involvement
during the course of the disease, with varied renal pathologic lesions
and diverse clinical features. A renal biopsy examined by routine light
microscopy, immunofluorescence, and electron microscopy contributes
toward diagnosis, prognostic information, and appropriate management.
Objectives.--(1) To review the clinical and various pathologic features of renal lesions in systemic lupus erythematosus patients. (2) To introduce the International Society of Nephrology and Renal Pathology Society Classification of Lupus Glomerulonephritis.
Data Sources.--A literature review, illustrations with original artwork, and tabulation of clinical and pathologic data of cases obtained from the authors' renal biopsy files examined during the last 8 years were used.
Conclusions.--The International Society of Nephrology/ Renal Pathology Society-sponsored Classification of Lupus Glomerulonephritis proposes standardized definitions of the various pathologic findings, describes clinically relevant lesions, incorporates prognostic parameters, and recommends a uniform way of reporting the renal biopsy findings. Lupus glomerulonephritis is divided into 6 classes primarily based on the morphologic lesions, extent and severity of the involvement, immune complex deposition, and activity and chronicity. Special emphasis is laid on describing qualitative as well as quantitative morphologic data and to include the accompanying tubulointerstitial disease and different vascular lesions, which have prognostic and therapeutic significance. This classification is intended to facilitate a higher degree of reproducibility, resulting in better patient care and more effective future clinical and translational research. Renal biopsy findings in systemic lupus erythematosus add new and independent parameters of prognostic significance to established clinical and genetic factors.
|Article Type:||Disease/Disorder overview|
Systemic lupus erythematosus
Kidney diseases (Diagnosis)
Immune system (Research)
Immune system (Physiological aspects)
Seshan, Surya V.
Jennette, J. Charles
|Publication:||Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165|
|Issue:||Date: Feb, 2009 Source Volume: 133 Source Issue: 2|
|Topic:||Event Code: 310 Science & research|
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease
caused by dysregulation of the immune system that involves almost all
organs in the body. (1) Renal involvement is observed in most SLE
patients at some point during the natural history of the disease, with a
significant proportion having an adverse outcome. (2,3) Nearly 50% of
SLE patients develop renal disease in the first year of diagnosis.
Approximately 20% of SLE patients with renal disease include children
(4) and older adults. Glomerular and microvascular lesions similar to
lupus may occur, although less frequently, in association with other
autoimmune diseases, such as rheumatoid arthritis, progressive systemic
sclerosis, dermatomyositis, rheumatic fever, mixed connective tissue
disease, and various noninfectious vasculitides. (1)
The correlation of clinical renal and serologic features with underlying renal pathologic findings is not absolute, having poor predictive value in nearly 30% to 50% of cases (5) (see also Table 1). The prevalence of SLE varies with race, sex, and age, the highest incidence being in African American females. Increased incidence of SLE within families also suggests a genetic predisposition. Systemic lupus erythematosus occurs predominantly in females of childbearing age, with a male to female ratio of 1:10. A definitive diagnosis of SLE is usually made when at least 4 of 11 diagnostic criteria put forth by the American Rheumatologic Association are met, (6) occurring either sequentially or simultaneously. They include skin manifestations (malar rash, photosensitivity, alopecia), oral ulcers, arthritis, serositis, renal disease, neuropsychiatric disease, hematologic abnormalities (anemia, hemolysis, leukopenia; <4000 x [10.sup.6]/L), thrombocytopenia (<100 000 x [10.sup.6]/L), positive serologic findings, titers of anti-nuclear antibodies, anti-DNA antibodies, and Smith antibodies. This was later modified by the addition of positive titers of anti-phospholipid antibodies, which are observed in 25% to 50% of SLE cases, a subset at risk for developing anti-phospholipid antibody syndrome causing intravascular thrombosis. (7) Although these serologic tests are generally diagnostic, the titers of the antibodies can fluctuate with time and disease activity. Kidney involvement contributes significantly to morbidity and mortality in SLE patients. (5,8)
Multisystemic clinical manifestations are not always reliable indicators of the presence or severity of underlying renal lesions. Moreover, the diverse renal pathologic findings in SLE present with a range of clinical renal syndromes, such as asymptomatic hematuria/proteinuria, nephrotic syndrome, or nephritic syndrome (Table 1). This may be accompanied by varying degrees of hypertension and renal dysfunction. (5,8) A meticulously performed examination of active urinary sediment in lupus nephritis may reveal granular casts, red blood cell casts, waxy casts, white blood cells, and oval fat bodies, also known as a telescoped sediment. A proportion of cases also manifest acute renal failure or chronic progressive renal insufficiency. Hematuria, varying degrees of proteinuria, and renal dysfunction are usually linked to proliferative lupus glomerulonephritis (LGN) with an active urine sediment. Nephroticrange proteinuria generally predominates in membranous LGN. In active lupus renal disease, both the classic as well as the alternate pathways of the complement cascade are activated, and serum levels of C3, C4, and C1q are often depressed. In a small number of patients, renal disease may precede the onset of clinical SLE by months or years. (8)
The basis for the induction of autoimmunity has been a subject of investigation for many years using experimental models. (9,10) In addition to a variety of altered T-cell-mediated immunologic functions, including emergence of autoreactive T and B cells, one of the hallmarks of autoimmunity is the formation of autoantibodies targeting tissue-specific antigens or more general cellular/extracellular matrix components (proteoglycans, laminin) and nuclear antigens (single- and double-stranded DNA, nucleosomes, histones, and other lesser-known nuclear proteins). (11) These processes may be triggered by the interaction of a multitude of host (immunologic, genetic, hormonal) and/ or environmental factors (photosensitivity, infections). In recent years, the role of Toll-like receptors (particularly types 3, 7, 8, and 9) of innate immunity and their interaction with adaptive immunity have led to new perspectives in elucidating the molecular basis of endogenous or exogenous triggers in the onset of autoimmune disease and, more importantly, immune complex-mediated lupus nephritis. (12,13) The primary source of autoantigens in SLE may be deranged and/or inhibited cellular apoptosis from a number of mechanisms, including abnormal T-cell receptor function, defective expression of Fas ligand affecting Fas receptor binding, and overexpression of bcl-2. (11,14) This results in the persistence of autoreactive T cells and allows the release of structurally abnormal nucleosomes, as well as excess intraglomerular generation of nucleosomes that contribute to glomerular immune deposits. Specific antibodies or antibody clustering have been shown to be predictive of clinical subsets of SLE, type and severity of renal disease, and prognosis of LGN. (15,16)
There is a strong association between proliferative LGN and serologic findings of high-titer anti-nuclear antibodies and double-stranded anti-DNA antibodies, complexed primarily with nucleosomes and histones. (17) These antibodies have significant nephritogenic potential, with a wide range of cross-reactivity to normal glomerular constituents, avidly binding to heparan sulfate and type IV collagen in the glomerular basement membranes (11) and the endothelial and mesangial surfaces. (18) Anti-C1q antibodies are postulated amplification factors for the immune complex in LGN. (19) Immune complexes may form in situ or arrive as circulating preformed complexes. The spectrum of glomerular lesions, including combined patterns, rarely seen outside the context of lupus, reflects the diverse specificity of autoantibodies and the physicochemical nature of the complexes formed. Studies have shown a seasonal pattern for the onset and activity of SLE that correlates with certain patterns of LGN, suggesting a common trigger and an additional factor in the pathogenesis of LGN. (20)
The pattern of immune complex deposition in the glomeruli is known to depend on the nature of the complexes, such as circulating levels of antigen antibody, specificity, and the avidity, size, and charge of the complexes. (16) In experimental models, chronic low levels of antigen and antibody as well as small cationic complexes tend to deposit in the subepithelial space, where they can cause proteinuria by mediating sublytic membrane attack complex injury to podocytes. (21) Intermediate-sized complexes with high affinity may initially lodge in the mesangial areas and may be cleared promptly or cause minimal or mild glomerular disease. However, influx of larger complexes extends to the subendothelial space with excessive deposition, which is in direct continuity with the mesangium. When large subendothelial aggregates are formed and/or when "clearing" mechanisms are defective, these tend to accumulate under the endothelium. Immune complex deposits in the subendothelial zone are in direct contact with cellular and humoral inflammatory effectors through the endothelial pores. Immunoglobulin (Ig) Fc regions and C3b in immune complexes engage leukocyte Fc receptors and complement receptors, causing leukocyte recruitment and activation. Since immune complexes are able to fix the complement readily, they in turn initiate the complement cascade, leading to recruitment of activated T cells and migration of macrophages, and they stimulate intrinsic glomerular cell proliferation and formation of terminal complement components (C5-C9) or membrane attack complex, which may be directly injurious to endothelium and basement membranes. Damage of endothelial cells leads to activation of platelets and glomerular cells producing cytokines, chemokines, and growth factors, further amplifying inflammation or initiating intravascular coagulation. Although the location of immune deposits, the ensuing intensity of inflammatory reaction, and glomerular response determine the type, severity, and extent of proliferative glomerular lesions, (21) both immunologic and other nonimmunologic processes influence the course of disease and progression. Inflammation evoked by immune complexes is modulated by cytokines produced by leukocytes and endogenous glomerular cells. (22)
KIDNEY BIOPSY IN SLE
As in other medical diseases of the kidney, the renal biopsies in SLE are routinely examined by light microscopy (LM), immunofluorescence microscopy (IF), and electron microscopy (EM) following optimal preservation, thin tissue sectioning (2-3 [micro]m thick), and use of special stains (periodic acid-Schiff, Jones silver, and trichrome) to comprehensively assess all renal parenchymal compartments (glomeruli, tubules, vessels, and interstitium).
A kidney biopsy in an SLE patient with any degree of clinical renal disease plays an important role in diagnosis and management. (23,24) It is useful in establishing an initial pathologic diagnosis early during the course of SLE, including the various glomerular lesions and the parameters indicating severity, activity, chronicity, and other concomitant lesions. Such renal biopsies may serve as a baseline for a subsequent course of renal disease and correlation with clinical findings. Sometimes, other SLE-related or unrelated renal lesions requiring a different treatment approach (25) or "silent lupus nephritis" of varying severity may become evident. (26) Such information will enable the clinician to select a specific treatment protocol to an individual patient.
Systematic studies of renal biopsies before and after treatment have provided valuable prognostic information, guiding further management and predicting outcome. (27-30) Multiple biopsies yield additional information to guide the clinician when performed as protocol biopsies, to plan an alternative therapy, following a change/transformation of the underlying renal pathologic lesion to a more aggressive or less active/indolent form, or due to persistent or new clinical renal findings. (27-30) A flare-up in clinical symptoms of SLE may or may not reflect reactivation of underlying renal disease, but an alteration in the urinary findings or serologic status (C3 level, titer of autoantibodies) aids in predicting potential renal involvement. Renal biopsy findings in SLE add new and independent parameters of prognostic importance to established clinical factors, such as race, male sex, creatinine levels at presentation, hypertension, significant proteinuria, positive serologic titers, and low complement levels. (31-33) Some of the limitations that pathologists may encounter during examination of a renal biopsy are sample location (cortex versus medulla) and specimen adequacy, number of glomeruli, heterogeneity of glomerular lesions within a biopsy, transitions from one type of lesion to another during the course of lupus nephritis and SLE (Table 2), advanced parenchymal lesions, and occasional lack of correlation with clinical parameters.
Although renal disease in SLE has been observed for more than a century, the classification of the spectrum of glomerular lesions was first attempted by a group of pathologists in Buffalo, NY, in 1974 under the auspices of the World Health Organization, based on biopsy pathology. (3,7) This was later modified and revised in 1982, (34) as well as 1995, (35) taking into account the LM, IF, and EM findings. Each class and subclass was made to reflect the variability of the renal lesions as well as to identify parameters of prognostic significance. Kidney biopsies are performed in patients with SLE to provide a diagnosis, to provide insight into the severity and activity (reversibility) of the kidney disease, to provide prognostic information, and to guide therapy. This requires a classification system that recognizes the range of pathologic lesions, correlation of the classes with clinical outcomes, and effective communication of the pathologic findings. A revision of the classification of lupus nephritis36 sponsored by the International Society of Nephrology (ISN) and the Renal Pathology Society (RPS) has addressed these issues (Tables 3 and 4). The main objectives were to standardize definitions of the pathologic lesions (Table 5), create better distinctions between classes, emphasize clinically relevant findings, and propose a uniform way of reporting the renal biopsy findings that would include appropriate details for prognosis and therapy. The ISN/RPS classification also intended to facilitate a higher degree of reproducibility among pathologists. This would help not only in patient care but also in understanding the medical literature dealing with LGN, including the results of new clinical trials.
PATHOLOGY OF LUPUS NEPHRITIS
A broad range of renal pathologic changes in SLE involve glomeruli, tubulointerstitial compartments, and vasculature characterized by nonproliferative, proliferative, inflammatory, and sclerotic lesions of different severities and extents. These may or may not fall strictly under specific clinical profiles (Table 1), but guide the type of therapy and prognosis. The pathologic features are highly variable from patient to patient.
The pathologic criteria for the various classes of LGN formulated in the now widely used ISN/RPS classification are described in Table 3 and in an abbreviated form in Table 4. (36) This schema was designed to accommodate centers around the world where EM is not a standard practice in examining renal biopsies and where limited resources may be available to perform routine EM. Although LM and IF yield considerable/reliable information with reasonable certainty regarding the specific class of LGN, along with the extent of reversibility or potentially treatable lesions, the application of EM is crucial in a proportion of cases for diagnosis, prognosis, and management. (28,29,37-40) Similar pathologic criteria should be applied for repeat biopsies to retain the uniformity of reporting and comparison.
Class I: Minimal Mesangial LGN
All 3 previous versions of the classification of lupus nephritis (1974, 1982, and 1995) included specimens with normal glomeruli by LM, EM, and IF in class I lupus nephritis. The ISN/RPS schema has omitted normal glomeruli by LM, EM, and IF from class I. The ISN/RPS class I includes specimens with glomeruli that appear normal by LM but have mesangial immune complex deposits by IF. (36) The capillary walls are generally of normal thickness by periodic acid-Schiff and silver staining with widely patent lumina (Figure 1). Tubuloreticular inclusions are observed frequently by EM in endothelial cells in class I LGN as well as all other classes of LGN, and even in SLE patients without LGN. A detailed ultrastructural examination of the glomerular lesions helps to confirm LM and IF pictures and identify subtle findings essential for making an initial diagnosis of lupus nephritis in an otherwise clinically silent SLE or lupus nephritis and in the absence of appropriate serologic markers when a corresponding immunofluorescence pattern of "full house" is noted. Patients with class I LGN may or may not manifest clinical renal symptoms and comprise a small fraction of lupus renal biopsies.
Class II: Mesangial LGN
Mesangial disease (deposits and/or proliferation) is a sine qua non of all classes of LGN, and this category denotes glomerular changes confined to mesangial areas (cellularity and matrix) of varying degrees by LM. No endocapillary proliferation, necrosis, or crescents are noted. Immunoglobulin (IgG, IgM, and IgA) and complement component (C3, C1q, C4, and properdin) full house deposits are observed by IF and granular dense deposits by EM, exclusively or predominantly in the mesangial areas (Figure 2). Occasional, scattered, small subepithelial or subendothelial deposits may be identified by IF/EM at this time, but these must not be extensive enough to cause capillary wall changes that are identifiable by LM. When such minimal capillary wall deposits are present, some pathologists add a comment in the report stating the potential for progression to class III or class IV lesions. The presence of small scattered or confluent deposits under the endothelium that can only be observed by EM increases the likelihood for transformation to a more severe or higher class of lupus nephritis, and thus requires close clinical follow-up.3,36 The tubulointerstitial compartment and arterial vessels are generally preserved. Clinically, nearly 60% of patients with class II lesions present with asymptomatic proteinuria (subnephrotic range), asymptomatic hematuria, or both with normal renal function (Table 1). Nephrotic-range proteinuria is not common in this class. This may be indicative of minimal-change disease (lipoid nephrosis). Although these glomerular lesions remain stable in most cases with close clinical monitoring of the systemic disease and supportive therapy, a significant number may progress to class III or class IV LGN.
Class III: Focal LGN
The definition of this category is proliferative glomerular lesions (segmental or global) involving less than 50% of all glomeruli examined. Because segmental lesions (portion of a glomerulus) are the most common feature in class III, the word segmental is omitted from the heading, in keeping with the original definition of less than 50% involvement of glomeruli (1974), thus allowing for occasional global lesions to be included. (36) However, in daily practice they are usually segmental endocapillary proliferative lesions with or without accompanying capillary wall (fibrinoid) necrosis, crescents (cellular, fibrocellular, and fibrous types), or segmental sclerosis (Figure 3, A and B). Any of the active lesions listed in Table 5 may be seen, often in a segmental distribution. Mild to moderate mesangial proliferation and deposits are also present in most cases. A small number of cases have segmental "fibrinoid" necrotizing lesions in the absence of conspicuous intraglomerular cell proliferation or immune deposits, a few with positive antineutrophil-cytoplasmic antibody serology, suggesting a different pathogenetic mechanism. (3,41) The glomerular lesions by light microscopy are further subdivided into categories with purely active lesions (A), active and chronic sclerosing lesions (A + C) or chronic (C) glomerular lesions (Table 3). (36) Typical immunofluorescence patterns with varying amounts of all 3 immunoglobulins, complement components (C3 and C1q), and both light chains ([lambda] and [kappa]) are observed globally in the mesangium in all glomeruli regardless of proliferative lesions, with focal capillary wall staining representing subendothelial and variable subepithelial deposits. Positive fibrin or fibrinogen staining is present in segments of necrosis; fibrinogen staining in capillary thrombi suggests a superimposed condition (thrombotic microangiopathy). The above findings of active and/or chronic (inactive) lesions (segmental scars) should be reported in the diagnostic line with a quantitative assessment reflecting predominantly active, mixture of active and chronic, or mostly chronic parameters. In contrast to IF, EM may be less sensitive in class III because of the focal distribution of the proliferative lesions (Figure 3, C and D), the variability in the extent and severity of disease, and sample size. The actual amount of glomerular deposits also varies within the same biopsy when an available glomerulus is studied by EM. When only focal segmental sclerosing lesions are present, class III-C is assigned to indicate a previous active episode that has progressed to scarring. The glomerular lesions can be accompanied by areas of active tubulointerstitial inflammation with or without tubular basement membrane deposits, or tubular atrophy and interstitial fibrosis in the chronic phase.
[FIGURE 1 OMITTED]
Clinical renal presentation of class III is more heterogeneous, spanning hematuria, proteinuria, a nephritic picture (Table 1) with active sediment, and nephrotic syndrome in a smaller group of patients. This may be accompanied by mild to moderate renal insufficiency in fewer than 25% of cases. The prognosis of patients with class III lesions also varies widely, from no change to progression to class IV and class V, as seen in subsequent renal biopsies (Table 2), whereas others recover, posting higher 5-year renal survival rates. (3)
[FIGURE 2 OMITTED]
Class IV: Diffuse LGN
This class has involvement of 50% or more of all glomeruli with segmental (S) or global (G) A or C lesions. (36) Class IV-G has global lesions in 50% or more of glomeruli, and class IV-S has segmental lesions in 50% or more of glomeruli. Class IV-S and class IV-G are further categorized by the presence of A, A + C, or C lesions (Tables 3 and 4). Active lesions (Figure 4, A through E) have varying degrees of large subendothelial deposits ("wire loop lesions"), hyaline thrombi, endocapillary cellular proliferation, inflammatory cell infiltration, fibrinoid necrosis with disruption of capillary basement membranes, and cellular crescents that generally have mesangial proliferation. Chronic glomerular lesions include segmental and global glomerulosclerosis and fibrocellular (Figure 4, F) and fibrous crescents (Table 5).
The subdivisions of class IV-S and class IV-G were included in the ISN/RPS classification because of a long-term lupus nephritis outcome study (>10 years) that demonstrated a poor prognosis for diffuse segmental (class IV-S) LGN compared with diffuse global (class IV-G) LGN or combined membranous and diffuse global LGN (class V + class IV-G). (42) This study and a subsequent study by Hill et al (43) also raise the possibility that class IV-G and class IV-S LGN are caused by different pathogenetic mechanisms. This subdivision may facilitate further studies regarding their possible pathogenetic mechanisms, clinical relevance, and prognostic significance.
In addition, other glomerular histologic variants of class IV include (1) extensive subendothelial deposits with minimal or no proliferative component, (2) diffuse severe mesangial proliferation with widespread subendothelial deposits, (3) diffuse, global endocapillary proliferation and inflammatory cell infiltration with minimal or moderate deposits, and (4) membranoproliferative pattern of glomerulonephritis, (36) thus demonstrating the heterogeneity of the glomerular patterns in this class of lupus nephritis. All of the active glomerular features (Table 5) may manifest fully with any degree of severity. Focal or widespread active interstitial inflammation and edema and active tubulitis may accompany the active glomerular disease. Vascular lesions that are most frequently encountered range from vascular immune deposits by IF but not LM to lupus vasculopathy with massive noninflammatory small arterial and arteriolar intimal deposits, thrombotic microangiopathy or, on rare occasions, necrotizing arteritis.
[FIGURE 3 OMITTED]
Generally, a full house IF pattern is found in class IV lesions, with occasional cases that are pauci-immune, usually class IV-S (Figure 5). Most deposits are located in the subendothelial and mesangial areas, with scattered or variable numbers of deposits under the epithelium as seen by EM (Figure 6, A and B). When subepithelial deposits exceed 50% of the capillary walls, the class V category should be reported in combination with class IV. In this situation, EM is a useful tool to make this distinction better than IF alone. Frequently, granular deposits along tubular basement membranes are associated with this active lesion.
In class IV as well as in other classes of LGN, a variety of ultrastructural features may be observed, including focal or diffuse organized deposits (admixed with granular type), such as (1) crystalline/fingerprint-like structures in 5% to 10% of cases, usually with a thickness of 10 to 15 nm of the thin curvilinear bands and having cross-striations with a periodicity (Figure 7, A)37; and (2) cryoglobulins composed of larger hollow tubular-type deposits measuring 50 to 100 nm in thickness and occasional Congo red-negative fibrillary deposits, occurring at random or in parallel bundles, composed of polyclonal immunoglobulins (Figure 7, B). (44) These fingerprint forms, which may not always be associated with cryoglobulinemia, (38,40,44) are more frequently observed in deposits around the glomerular basement membranes than in mesangial areas and are also found along tubular and peritubular capillary basement membranes and arteriolar walls. Such organized deposits are rarely seen in renal lesions long before the actual onset of SLE. (45) Patients with hepatitis C-associated cryoglobulinemic glomerulonephritis (46) and monoclonal immunoglobulin diseases secondary to lymphoproliferative or plasma cell myeloma disorders (47) may have similar organized tubular or fibrillary substructure of the glomerular deposits. Intracytoplasmic tubuloreticular inclusions are noted within the endoplasmic reticulum of the endothelial cells and infiltrating lymphocytes in lupus nephritis (Figure 7, C). Frequent tubuloreticular inclusions, and especially confronting cylindrical cisternae, are associated with minimally treated and clinically active disease. 48 These are believed to be induced by the high serum levels o, elaborated by the activated T lymphocytes in patients with SLE. These inclusions are not specific for lupus and may also be observed in patients with human immunodeficiency virus (HIV) and, rarely, other viral infections (hepatitis B and C) in the kidney.
[FIGURE 4 OMITTED]
[FIGURE 5 OMITTED]
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Class V: Membranous LGN
This subset of lupus nephritis (membranous type) is diagnosed when immune deposits are found in the basement membranes under the glomerular visceral epithelial cells, in a global or segmental distribution involving more than 50% of capillary basement membranes. Any degree of mesangial proliferation may accompany this lesion. The incidence of this lesion ranges from 10% to 30% in various reports. The glomerular capillary walls may appear normal by LM in early stages with positive IF, or diffusely thickened, involving most or all of the glomeruli in a global distribution. This is visualized by periodic acid-Schiff and Jones silver stains as pinholes and basement membrane spikes alternating with lucencies on the outer aspect of the glomerular basement membranes (Figure 8, A). Subepithelial deposits, when present in substantial amounts, appear by trichrome stain as fuchsinophilic granules on the outer aspect of glomerular basement membrane. In advanced cases of class V, double contours of the capillary walls may be seen due to intramembranous deposits, fusion of spikes, and new basement membrane formation. Since this is a diffuse process, IF shows a typical, global coarsely to finely granular pattern of glomerular capillary wall staining, usually for all 3 immunoglobulins--IgG being the most intense (Figure 8, B)--and complement components C3 and C1q, as well as in the mesangium. The characteristic, granular, and irregular subepithelial and/or intramembranous dense deposits are noted in the glomerular basement membrane by EM (Figure 8, C and D), some of them having a penetrating property traversing part of or the entire thickness of the lamina densa. (3)
Several clinical and pathologic parameters can be used to distinguish a non-lupus membranous GN from membranous LGN when overt SLE manifestations are not readily expressed, including hypocomplementemia, a full house fluorescence pattern, the presence of mesangial hypercellularity/ deposits, and the finding of occasional subendothelial deposits and tubuloreticular inclusions in endothelial cells by EM. (39) When a focal segmental or diffuse (endocapillary) proliferative LGN is observed concurrently with membranous LGN, they are designated as mixed class III + V or class IV + V, respectively, because these assume the behavior of proliferative lupus nephritis.
[FIGURE 7 OMITTED]
Characteristically, patients with class V present with proteinuria or, more often, nephrotic syndrome (nearly 80%; Table 1) and normal renal function. Hematuria may be observed in a substantial number of cases, along with hypertension. However, except for positive anti-nuclear antibody test, varying low C3 levels, low or absent titers of anti-double-stranded DNA in more than 50% of patients, a higher percentage being positive for anti-Smith, anti-ribonuclear protein, and Sjogren syndrome B antigen are noted, frequently together with only mild extrarenal lupus symptoms. (49)
Class VI: Advanced Sclerosing LGN
This represents a late stage of LGN and a culmination of multiple relapses of lupus nephritis, leading to progressive chronic tubulointerstitial scarring, global glomerular sclerosis, and vascular sclerosis. A diagnosis of class VI LGN is made when 90% or more of glomeruli are globally sclerotic. (36) This suggests that there are no reasonably treatable lesions; however, this conclusion should be substantiated by clinical and laboratory findings.
Active/proliferative LGN is often accompanied by varying degrees of tubulointerstitial inflammation with or without tubular basement membrane and vascular immune complex deposits demonstrable by IF and EM. (3) The active inflammatory infiltrate is generally composed of mainly activated T lymphocytes, plasma cells, histiocytes, and a few polymorphs, with focal tubulitis accompanied by interstitial edema and tubular cell degenerative changes. The onset of chronic renal disease is characterized by tubular atrophy, chronic interstitial inflammation, and interstitial fibrosis, which contributes greatly to impairment of renal function and progression of lupus nephritis. Howie et al (50) have developed a morphometric index of chronic renal parenchymal damage in lupus nephritis, which essentially correlates the extent of tubular atrophy and interstitial fibrosis in predicting poor prognosis, regardless of the type of glomerular lesion.
Vascular lesions are an integral part of the spectrum of autoimmune diseases, including SLE, scleroderma, rheumatoid arthritis, overlap, and other lupuslike syndromes that do not fulfill the American Rheumatism Association's criteria for classic SLE. (51) Vascular complications in SLE lead to a variety of clinical symptoms depending on the site/organ, severity, size and type of vessel involved, temporal nature (acute or chronic), and host/genetic factors. (52) They present as the initial clinical symptom of the systemic disease, but rarely of renal limited disease. A number of different types of vascular lesions affecting almost all calibers of vessels have been observed in the setting of lupus nephritis. (53-55) They include asymptomatic or uncomplicated vascular immune complex deposits, lupus vasculopathy (noninflammatory, eosinophilic, intimal immune complex deposition involving small arteries and arterioles; Figure 9, A), acute/chronic thrombotic microangiopathy (glomeruli, arterial vessels; Figure 9, B and C), and rarely transmural necrotizing vasculitis (intrarenal arterioles and small arteries; Figure 9, D and E). These vascular lesions may accompany mostly the proliferative classes of lupus nephritis, whereas thrombotic microangiopathy (glomerular and/or vascular) may develop in all classes of lupus nephritis, and sometimes even in the absence of other forms of renal parenchymal disease. Evidence of endothelial damage (swelling, separation from capillary wall, and degenerative changes) suggesting isolated or concurrent thrombotic microangiopathy due to anti-phospholipid antibodies is yet another reason for ultrastructural study of renal biopsies from patients with SLE. Degenerative or sclerosing vascular lesions are found following healed acute or chronic vascular injury. Vascular lesions in SLE contribute significantly to the development of hypertension, progressive course, and chronic renal parenchymal disease. Thus, proper diagnosis and identification of the type, extent, and severity of the lesion have considerable prognostic and therapeutic value. (53-55) The pathogenetic mechanisms leading to vascular lesions in SLE primarily cause endothelial injury due to one or more factors, such as immune complexes, cell-mediated mechanisms, anti-phospholipid antibodies, anti-endothelial antibodies, superimposed anti-neutrophil cytoplasmic antibodies, host/genetic factors, and concomitant activation of coagulation factors.
[FIGURE 8 OMITTED]
The higher rate of prevalence of anti-phospholipid antibodies in a patient with SLE or lupus nephritis is linked to increased risk of renal and/or extrarenal thrombotic manifestations, commonly recurrent venous thrombosis, pulmonary emboli, fetal loss during pregnancy, and cerebrovascular accident. Renal thromboticmicroangiopathy in the absence of immune complex-mediated glomerular lesions showing fresh organizing thrombi; cellular, mucoid or fibrous intimal hyperplasia; or occlusion of small arteries/arterioles, glomerular thrombi, and EM evidence of glomerular endothelial injury are noted. (56,57) These bore no relationship to specific classes of LGN, titers of anti-phospholipid antibodies, or other lupus serologies. The presence of circulating anti-phospholipid antibody syndrome is strongly associated with a greater frequency of hypertension and extensive interstitial fibrosis, and thus an increased risk of chronic renal insufficiency in patients with lupus nephritis. (58)
[FIGURE 9 OMITTED]
ACTIVITY AND CHRONICITY
Although this concept was considered previously by identifying certain histologic parameters with prognostic significance, (3) activity and chronicity indices developed by the National Institutes of Health and using semiquantitative scoring based on specific morphologic features have been used to guide therapy and assess prognosis. (59) The initial active renal lesions were not helpful to prognosticate the long-term outcome, but they provide a guide for the type of therapeutic protocol to be instituted based on the presence and severity of active and chronic lesions. In contrast, the extent of the chronic lesions (fibrous crescents, global glomerulosclerosis, tubular atrophy, and interstitial fibrosis) showed better correlation toward predicting prognosis. Hill et al, (27,28) in a large prospective study of protocol biopsies of diffuse lupus nephritis in the initial and 6-month periods, observed that the renal pathologic findings in the first biopsy, although useful for appropriate therapy, had no long-term predictive value. However, analysis of second biopsy findings at the 6month interval were strongly predictive of doubling of serum creatinine and further progression of renal disease. Some of the important parameters were persistent subendothelial and mesangial deposits, overall intensity of IF (particularly C3), cellular crescents, and infiltrating (glomerulus/ tubular) macrophages. (28) The magnitude of the nephritogenic potential of macrophage infiltration in proliferative glomerulonephritides, being highest in lupus nephritis and cryoglobulinemic GN, was demonstrated by Ferrario et al. (60) The ISN/RPS Lupus Nephritis Consensus Conference has clearly defined the pathologic features of active and chronic lesions, which may allow for better reproducibility. The ISN/RPS system recommends that a detailed microscopic description should be provided that includes the qualitative and quantitative assessment of all active and chronic renal parenchymal findings, along with tubulointerstitial and vascular lesions. Furthermore, the diagnostic line should indicate the predominant type of glomerular lesion, including actual number with necrosis and/or crescents and global sclerosis, and the extent and type of tubulointerstitial and vascular lesions. Based on the above suggestions, pathologists may not be required to add an activity or chronicity score (National Institutes of Health or another system), although a sizable proportion of clinicians prefer it to be mentioned in the diagnostic line.
Although significant morphologic refinement and further clarification of the glomerular lesions have been achieved in the recent ISN/RPS classification, (36) this is a constantly evolving process incorporating emerging new data, indicative of prognostic value and outcome. Further validation and reproducibility studies based on these categories will be necessary regarding their relevance to clinical renal disease, correlations with outcome, and histologic differences. When a retrospective biopsy study of 60 Japanese patients diagnosed with LGN was analyzed and compared with the World Health Organization 1995 schema, a higher histologic consensus was obtained using the ISN/RPS 2004 classification (98% vs 83%; P = .008), and it provided beneficial prognostic information to predict long-term outcome as well as to devise optimal therapy to delay end-stage renal failure. (61) Hill and coworkers (43) went further to assess the data of subgroups of diffuse LGN in 76 cases: 2 protocol biopsies 6 months apart from their previous studies. (27,28) The class IV-G patients had a greater degree of proteinuria, low C3 level, increased active glomerular deposits and macrophage infiltration, and 0% 10-year survival with persistent lesions. In cases with class IV-S, there was more glomerular fibrinoid necrosis with relatively pauci-immune segmental lesions showing mainly mesangial deposits and 63% 10-year renal survival with persistent lesions. In contrast, another renal biopsy study conducted using 33 cases of class IV lupus nephritis applied ISN/RPS classification criteria and demonstrated no significant differences in outcome after average follow-ups of 38 and 55 months in the class IV-S and class IV-G groups, respectively. (62) However, the length of the follow-up may be shorter for a reasonable conclusion.
A survey pertaining to the utility and problems related to the ISN/RPS classification was conducted by the research committee of the RPS in 2006-2007 (chair, Dr Terrence Cook, United Kingdom) among its members, with 55 responses. The results revealed that 85% are using this classification of LGN in their nephropathology practice. Although more studies are needed to justify the clinical significance for the division of class IV-S and class IV-G types, the classification generally has shown a higher degree of reproducibility, and the simplified, easy-to-use schema is recognized. This was also reinforced by an interobserver United Kingdom study and a 3-year assessment of the ISN/RPS classification. (63,64) A common area of difficulty raised by more than 25% of the participants of the survey was the assessment of globally sclerosed glomeruli in classes III, IV, and V, and their relationship to a prior episode of active lesions or secondary to progressive vascular disease. Ongoing education of the clinicians of the various pathologic features and significance of the ISN/RPS classification by the pathologists helps in improving communication between them.
OTHER RENAL LESIONS IN SLE
Apart from the immune complex-mediated glomerular disease in SLE, other forms of renal disease with varied pathologies are also observed with a lesser frequency. (3,25) They include minimal-change nephrotic syndrome (lipoid nephrosis) and focal segmental glomerulosclerosis, which may be due to podocytic injury induced by abnormal cytokines from T-cell activation. (3) Other nonlupus renal lesions documented regardless of clinical or serologic activity of SLE are secondary amyloidosis, IgM nephropathy, thin basement membrane disease, and hypertensive nephrosclerosis (25) following a renal biopsy.
The finding of autoimmune clinical symptoms and lupus-like nephritis in patients with HIV infection has led to consideration of the pathogenetic relationship between retroviral infection and SLE. The induction of immune dysregulation by HIV may result in hypergammaglobulinemia, suggesting an abnormal polyclonal B-cell activation and immune complex glomerulonephritis in these patients. The renal lesions have preceded, occurred concurrently, or followed the diagnosis of HIV infection, manifesting proliferative forms as well as membranous lupus nephritis or lupuslike nephritis. (65,66)
Has routine histopathologic examination of the renal lesions in SLE reached its limitation? Recent advances in genetic, molecular, and immunopathogenetic mechanisms underlying SLE as well as the variability of renal injury in lupus nephritis have identified genetic differences in the expression of chemokines, cytokines, and polymorphism of Ig receptors in the peripheral blood monocytes and in renal tissue. (67-71) Gene expression profiling, by applying cDNA microarray analysis, real-time polymerase chain reaction, and high-density oligonucleotide microarray, was used. Examples include T-lymphocyte antigens and receptor pathways, various chemokine/cytokines and their receptors, types I and II interferon family endothelial adhesion molecules, and genes induced by interferons.
The factors driving the different glomerular patterns, severity of lesions, and those contributing to progression in lupus nephritis include ethnicity, age/sex, relapses, hypertension, specific serologic markers, and genetic predisposition. African Americans, Hispanics, and certain Asian women disclose higher incidences of lupus nephritis, increased severity of proliferative glomerular lesions, and progression to end-stage renal disease, most probably related to genetic, environmental, and socioeconomic factors. (31-33,72,73)
These and other studies may aid in identifying susceptibility to lupus nephritis or to specific renal lesions, prevalence in different populations, markers of activity, diagnostic parameters, predictors of prognosis, and to develop possible effective therapeutic strategies against specific targets in different patient groups. These investigations conducted at the experimental and clinical levels illustrate that genetic variability with a common phenotype may also manifest differences in response to a given therapeutic/ immunosuppressive regimen as well as outcome.
We thank Steven Bowe, BA, and Michael Ganger, MS, for preparation of the manuscript and technical assistance with illustrations.
Accepted for publication March 27, 2008.
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Surya V. Seshan, MD; J. Charles Jennette, MD
From the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY (Dr Seshan); and the Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill (Dr Jennette).
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Surya V. Seshan, MD, Department of Pathology and Laboratory Medicine,Weill Cornell Medical College, NewYork-Presbyterian Hospital, 525 E 68th St, Starr 1002, New York, NY 10065 (e-mail: firstname.lastname@example.org).
Table 1. Frequency of Clinical Renal Manifestations in Various Classes of Lupus Glomerulonephritis (LGN): 541 Patients * ISN/RPS Class, % II III I (n = 54) (n = 107) Clinical Features (n = 5) ([dagger]) ([double dagger]) Asymptomatic hematuria 40 19 22 Asymptomatic proteinuria 40 42 25 Nephrotic syndrome 20 15 17 ([paragraph]) Nephritic syndrome # ... 20 34 Acute renal failure ** ... 4 2 Chronic renal failure ... ... ... ISN/RPS Class, % IV-G IV-S V (n = 111) (n = 87) (n = 159) Clinical Features ([section]) ([section]) ([parallel]) Asymptomatic hematuria 4 6 5 Asymptomatic proteinuria 7 6 13 Nephrotic syndrome 40 38 65 ([paragraph]) Nephritic syndrome # 27 26 7 Acute renal failure ** 18 16 2 Chronic renal failure 4 8 8 ISN/RPS Class, % VI (n = 18) Clinical Features Asymptomatic hematuria ... Asymptomatic proteinuria ... Nephrotic syndrome 11 ([paragraph]) Nephritic syndrome # ... Acute renal failure ** ... Chronic renal failure 89 ([double dagger]) * Combined classes V + III: 68; combined classes V + IV: 37. Bold, italic numbers indicate common clinical renal manifestations of the various classes of LGN; ellipses represent no cases cited. ISN/RPS indicates International Society of Nephrology/Renal Pathology Society. ([dagger]) More than 80% of class II LGN patients presented with asymptomatic hematuria/proteinuria or nephritic syndrome. Nephrotic syndrome was associated with minimal-change disease, and acute renal failure was secondary to acute tubular injury. ([dagger]) Class III patients presented with hematuria/nephritic syndrome in more than 55% of cases, and 17% presented with nephrotic syndrome. ([section]) Most (85%) class IV (global [G] and segmental [S]) patients manifested nephrotic/nephritic syndrome or acute renal failure. Most of the combined classes III + V and classes IV + V are also included in the class III and class IV groups, respectively. ([parallel]) Nearly 80% of class V patients presented with proteinuria/nephrotic syndrome. ([paragraph]) Nephrotic syndrome: edema, proteinuria (<3.0 g/24 h), hypoalbuminemia. # Nephritic syndrome: hematuria, proteinuria, hypertension, and/or varying degrees of renal insufficiency, active urinary sediment. ** Acute renal failure: sudden, sustained decline in glomerular filtration rate, usually associated with azotemia and a fall in urine output. ([double dagger]) Chronic renal failure: slow, progressive rise in creatinine, hypertension with or without hematuria, and proteinuria. Table 2. Class Transformation During the Course of Lupus Glomerulonephritis (LGN): 85 Patients * Second Initial Kidney Biopsy ISN/RSP Class, % Kidney Biopsy II III IV-G ISN/RPS I (n = 11) n = 18) (n = 42) Class ([dagger]) (n = 1) ([double dagger]) ([section]) ([parallel]) I ... ... ... ... II ... 9 5 10 III ... 37 28 19 IV-G 100 36 17 28 IV-S ... ... 33 10 V ... 9 17 10 VI ... 9 ... 23 Second Initial Kidney Biopsy ISN/RSP Class, % Kidney Biopsy IV-S V ISN/RPS (n = 3) Class ([dagger]) ([paragraph]) (n = 10) I ... ... II ... ... III 67 20 IV-G ... 20 IV-S 33 ... V ... 30 VI ... 30 * Bold, italic numbers represent unchanged classes in second renal biopsies; ellipses represent no cases cited. ISN/RPS indicates International Society of Nephrology/Renal Pathology Society; G, global; and S, segmental. ([dagger]) The second renal biopsy was performed from 6 months to 10 years after the initial kidney biopsy. ([double dagger]) Class II (mesangial) LGN cases, although small in number, have shown progression to focal, diffuse, or membranous LGN during the course of systemic lupus erythematosus. ([section]) Although 28% of class III (focal) LGNs have remained unchanged in subsequent biopsies, 50% have converted to class IV (G and S) LGN, and 17% also show class V (membranous) LGN. ([parallel]) Class IV (diffuse) global LGN has shown recovery of the lesions (following treatment) in nearly 30% of cases to classes II and III, whereas 28% have remained the same with additional chronic/sclerosing changes, and the rest disclosed class IV--segmental and class V, and nearly a quarter of them progressed to class VI--advanced sclerosing LGN in follow-up biopsies. ([paragraph]) Very few class IV (diffuse) segmental LGN cases were rebiopsied to observe a significant trend. Table 3. International Society of Nephrology/Renal Pathology Society Classification of Lupus Nephritis (LN) ([dagger]) Class I Minimal mesangial LN Normal glomeruli by light microscopy (LM), but mesangial immune deposits by immunofluorescence microscopy (IF). Class II Mesangial proliferative LN Purely mesangial hypercellularity of any degree or mesangial matrix expansion by LM, with mesangial immune deposits. There may be a few isolated subepithelial or subendothelial deposits visible by IF or electron microscopy (EM), but not by LM. Class III Focal LN * Active or inactive focal, segmental or global endo-or extracapillary glomerulonephritis (GN) involving <50% of all glomeru-li, typically with focal subendothelial immune deposits, with or without mesangial alterations. III (A): Active lesions: focal proliferative LN III (A/C): Active and chronic lesions: focal proliferative and sclerosing LN III (C): Chronic inactive lesions with glomerular scars: focal sclerosing LN Class IV Diffuse LN * Active or inactive diffuse, segmental or global endo-or extracapillary GN involving [greater than or equal to] 50% of all glomeruli, typically with diffuse subendothelial immune deposits, with or without mesangial alterations. This class is divided into diffuse segmental (IV-S) LN when [greater than or equal to] 50% of the involved glomeruli have segmental lesions, and diffuse global (IV-G) LN when [greater than or equal to] 50% of the involved glomeruli have global lesions. Segmental is defined as a glomerular lesion that involves less than half of the glomerular tuft. This class includes cases with diffuse wire loop deposits but with little or no glomerular proliferation. IV-S (A): Active lesions: diffuse segmental proliferative LN IV-G (A): Active lesions: diffuse global proliferative LN IV-S (A/C): Active and chronic lesions: diffuse segmental proliferative and sclerosing LN IV-G (A/C): Active and chronic lesions: diffuse global proliferative and sclerosing LN IV-S (C): chronic inactive lesions with scars: diffuse segmental sclerosing LN IV-G (C): chronic inactive lesions with scars: diffuse global sclerosing LN * Indicate the proportion of glomeruli with active and with sclerotic lesions * Indicate the proportion of glomeruli with fibrinoid necrosis and/or cellular crescents * Indicate and grade (mild, moderate, severe) tubular atrophy, interstitial inflammation and fibrosis, severity of arteriosclerosis or other vascular lesions Class V Membranous LN Global or segmental subepithelial immune deposits or their morphologic sequelae by LM and by IF or EM, with or without mesangial alterations Class V LN may occur in combination with class III or IV in which case both will be diagnosed; may show advanced sclero-sis Class VI Advanced sclerotic LN [greater than or equal to] 90% of glomeruli globally sclerosed without residual activity ([dagger]) Reprinted with permission from the authors. (36) Table 4. Abbreviated International Society of Nephrology/Renal Pathology Society Classification of Lupus Nephritis (2003) * Class I Minimal mesangial lupus nephritis Class II Mesangial proliferative lupus nephritis Class III Focal lupus nephritis ([dagger]) Class IV Diffuse segmental (IV-S) or global (IV-G) lupus nephritis ([dagger]) Class V Membranous lupus nephritis ([section] Class VI Advanced sclerosing lupus nephritis * Indicate and grade (mild, moderate, and severe) tubular atrophy, interstitial inflammation and fibrosis, severity of arteriosclerosis, or other vascular lesions. Reprinted with permission from the authors. (36) ([dagger]) Indicates the proportion of glomeruli with active and with sclerotic lesions. ([double dagger]) Indicates the proportion of glomeruli with fibrinoid necrosis and cellular crescents. ([section]) Class V may occur in combination with class III or IV, in which case both will be diagnosed. Table 5. Active and Chronic Glomerular Lesions * Active lesions Endocapillary hypercellularity, with or without leukocyte infiltration and with substantial luminal reduction Karyorrhexis Fibrinoid necrosis Rupture of glomerular basement membrane Crescents, cellular or fibrocellular Subendothelial deposits identifiable by LM (wireloops) Intraluminal immune aggregates (hyaline thrombi) Chronic lesions Glomerular sclerosis (segmental, global) Fibrous adhesions Fibrous crescents * Reprinted with permission from the authors.36 LM indicates light microscopy.
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