Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

SAVE OFFLINE

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

Official reprint from UpToDate® www.uptodate.com ©2019 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Diagnosis and classification of renal disease in systemic lupus erythematosus Authors: Andrew S Bomback, MD, MPH, Gerald B Appel, MD Section Editors: Richard J Glassock, MD, MACP, David S Pisetsky, MD, PhD Deputy Editor: Albert Q Lam, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2019. | This topic last updated: May 08, 2018.

INTRODUCTION Renal involvement is common in systemic lupus erythematosus (SLE). An abnormal urinalysis with or without an elevated plasma creatinine concentration is present in a large proportion of patients at the time of diagnosis of lupus nephritis. The most frequently observed abnormality in patients with lupus nephritis is proteinuria [1-3]. Up to 10 percent of patients with lupus nephritis develop end-stage renal disease, and patients with lupus nephritis have a higher mortality than SLE patients without lupus nephritis [1,4,5]. Clinical findings underestimate the true frequency of renal involvement, as some patients may (rarely) have significant pathologic abnormalities without any clinical signs of renal involvement. (See 'Silent lupus nephritis' below.) There are several types of renal disease in SLE (most commonly, immune complex-mediated glomerular disease), which are usually differentiated with a kidney biopsy. In addition, renal diseases that are unrelated to lupus may be seen [2,3]. An overview of the epidemiology, pathogenesis, and classification of lupus nephritis will be presented here. The indications for renal biopsy and the approach to therapy in the different types of lupus nephritis are discussed separately. (See "Indications for renal biopsy in patients with lupus nephritis" and "Treatment and prognosis of diffuse or focal proliferative lupus nephritis" and "Clinical features and therapy of lupus membranous nephropathy".)

PATHOGENESIS

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&s…

1/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

The pattern of glomerular injury seen in SLE (and in other immune complex-mediated glomerular diseases) is primarily related to the site of formation of the immune deposits, which are primarily due to anti-double-stranded DNA antibodies (anti-dsDNA, or anti-DNA). These antibodies bind DNA in various forms, such as DNA in the form of nucleosomes, which consist of dsDNA wound around a core histone octamer [4]. Anti-DNA immune complex formation — These immune complexes are primarily composed of DNA and anti-DNA. However, immune complexes may also have as their components chromatin, C1q, laminin, Sm, La (SS-B), Ro (SS-A), ubiquitin, and ribosomes [6-13]. In addition to forming immune complexes with DNA, some anti-DNA antibodies may bind directly to components of the glomerular basement membrane (GBM) and mesangium [14,15]. The immune deposits in lupus nephritis can occur in the mesangium, subendothelial, and/or subepithelial compartments of the glomerulus. Deposits in the mesangium and subendothelial space are proximal to the GBM and are therefore in communication with the vascular space. As a result, activation of complement (typically via the classical pathway) with the generation of the chemoattractants, C3a and C5a, results in the influx of neutrophils and mononuclear cells. These changes are manifest histologically by a mesangial or focal or diffuse proliferative glomerulonephritis and clinically by an active urine sediment (red cells, white cells, and cellular and granular casts), proteinuria, and, often, an acute decline in renal function. Although deposits in the subepithelial space can also activate complement, there is no influx of inflammatory cells, since the chemoattractants are separated from the circulation by the GBM. Thus, injury is limited to the glomerular epithelial cells, and the primary clinical manifestation is proteinuria, which is often in the nephrotic range. Histologically, these patients most commonly have membranous nephropathy. The site of immune complex formation is related to the characteristics of both the antigen and antibody: ●

Large intact immune complexes or anionic antigens (which cannot cross the anionic charge barrier in the glomerular capillary wall) are deposited in the mesangium and subendothelial space [6,7]. The degree of immune deposition then determines whether the patient develops mild disease limited to the mesangium or a more severe focal or diffuse proliferative glomerulonephritis. Experimental studies suggest that there are two primary mechanisms by which subepithelial deposits may form: a cationic antigen that can cross the GBM; and an autoantibody directed against epithelial cell antigens. (See "Mechanisms of immune injury of the glomerulus".)

●

Another important determinant of the site of immune complex formation may be related both to the charge of the antibody and to its antigen-binding region. The antibody may bind to

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&s…

2/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

antigens at different sites in the glomerular capillary wall, thereby leading to different histologic and clinical manifestations [11,16,17]. Some data suggest that intraglomerular membrane-associated nucleosomes are targeted by anti-dsDNA autoantibodies [18]. Other mechanisms — Not all circulating anti-DNA antibodies in SLE are necessarily nephritogenic. One study, for example, compared 14 patients with both anti-DNA antibodies and active nephritis with 14 patients who had anti-DNA antibodies but no nephritis. The plasma antiDNA antibodies in these clinically disparate groups were indistinguishable based upon isotype, charge, or cross-reactivity with histones [19]. Although not examined in the patients of this study, other studies have shown that anti-DNA antibodies capable of fixing complement are more nephritogenic [20]. In addition, the nephrotoxicity of anti-DNA may not require immune complex formation. Anti-DNA antibodies appear to bind to human mesangial cells in vitro and induce production of proinflammatory substances [21,22]. In an in vitro system, for example, anti-DNA isolated during active lupus nephritis induced mesangial cell production of interleukin-1 (and other proinflammatory substances), which in turn increased synthesis of hyaluronan (an extracellular matrix component that accumulates during tissue injury and recruits lymphocytes) [22]. The plasma cells that secrete these autoantibodies have been located not just in the spleen and bone marrow, but also in the kidney [23]. Thus, the kidney may be a major site of autoreactive plasma cells in lupus nephritis. Some data suggest that autoantibodies against C1q, a complement component, may correlate with lupus nephritis [24-26]. The mechanism of action of these antibodies may be initiated by the general deposition of immune complexes on the GBM, with C1q being fixed on these immune complexes [27]. Subsequent binding of anti-C1q antibodies to C1q activates complement, resulting in an influx of inflammatory cells. It has also been suggested that the immunoglobulin G (IgG) subclass may be a determinant of the inflammatory response that is induced by immune complex deposition. IgG1 and IgG3 fix complement, while IgG2 does so less avidly, and IgG4 does not fix complement [28]. Thus, the latter two subclasses are less likely to induce inflammation. Consistent with this hypothesis are the observations that anti-DNA antibodies associated with diffuse proliferative glomerulonephritis tend to be IgG1 and IgG3 [29], while the immune deposits in membranous nephropathy are more likely to be IgG2 and IgG4 [30]. However, as noted above, the separation of the immune deposits from inflammatory cells in the circulation by the GBM may be a more important reason why an inflammatory change is lacking in membranous nephropathy [7]. Neutrophils and neutrophil extracellular traps (NETS) may add to antigen-specific autoantibody production facilitating inflammation, endothelial damage, and local interferon alpha production in the kidney [1].

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&s…

3/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

Immune complex deposition can activate other arms of the inflammatory response: ●

Upregulation and activation of adhesion molecules on endothelium can result in the recruitment of proinflammatory leukocytes and the initiation of autoimmune injury [31]. (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation".)

●

Activated glomerular cells, infiltrating macrophages, and T cells produce inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), tumor growth factor-beta, interferon-gamma, chemokines, and platelet-derived growth factor. All of these inflammatory mediators have the potential to extend renal injury [32-35]. Activated platelets may also contribute to mesangial cell proliferation [36].

Genetics — A variety of genetic factors reportedly predispose patients to the development of SLE and influence the clinical picture of renal disease in SLE [37]. (See "Epidemiology and pathogenesis of systemic lupus erythematosus", section on 'Genetic factors'.) The increased frequency and severity of lupus nephritis among African Americans has led to the examination of genetic factors that might predispose to lupus nephritis [38-43]. Polymorphisms in the immunoglobulin receptor alleles Fc-gamma-RIIa-H131, present on macrophages, have been associated with susceptibility to lupus nephritis in some studies [38,42], although conflicting data exist [39]. Other studies have noted an association between polymorphisms in the Fc-gammaRIIIa-F158 receptor allele and Fc-gamma-RIIIb and lupus nephritis [40,41]. These polymorphisms result in alterations of the binding avidity of the receptors to their specific IgG subclasses [40]. It is hypothesized that this change permits the inappropriate deposition of circulating immune complexes in the kidney (and elsewhere) due to inadequate clearance by hepatic and splenic macrophages [38]. These differences may contribute to a worse prognosis in lupus nephritis. As an example, African Americans have higher frequencies of certain Fc-gammaRIIa-R131 alleles associated with phagocytosis of IgG2 immune complexes [38]. Two APOL1 gene variants that are found almost exclusively in African Americans have been associated with glomerulosclerosis and disease progression in a number of disorders including lupus nephritis [44,45]. (See "Clinical features, diagnosis, and treatment of hypertensive nephrosclerosis" and "HIV-associated nephropathy (HIVAN)".)

EPIDEMIOLOGY Most patients with SLE will have clinical evidence of renal disease, usually an abnormal urinalysis, at some point in the course of their disease. Clinically evident renal disease eventually occurs in approximately one-half of patients with SLE [46-52]. Study-to-study variations in prevalence estimates of lupus nephritis may be due in part to racial differences in disease prevalence and/or

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&s…

4/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

risk of nephropathy, as well as varying definitions and/or disease ascertainment [48,52-54]. The following summarizes the three largest available cohort studies [46,49-51]: ●

Among 1000 consecutive patients from 12 clinical centers in Europe, 16 percent had nephropathy (defined as protein excretion that was >0.5 g/day [or 3+ on dipstick], cellular casts, or unexplained elevation of the serum creatinine by at least 0.8 mg/dL [71 micromol/L]) at the time of SLE diagnosis [46]. During 10 years of prospective follow-up, nephropathy developed in 28 percent, although it was unclear whether this represented only new cases or also included recurrent disease [49].

●

In another report of 1378 patients with SLE in the United States, renal disease (defined as protein excretion that was >0.5 g/day, ≥5 red blood cells per high-power field, serum creatinine that was ≥1.5 mg/dL [133 micromol/L], or requiring dialysis or transplant) was present in 32 percent of patients within one year of diagnosis [50]. At a mean disease duration of nine years, 47 percent had protein excretion that was >0.5 g/day, and 6 and 4 percent had decreased glomerular filtration rate and end-stage renal disease, respectively [51].

●

Using billing data from the United States Medicaid population (which mostly includes ethnic and racial minorities living in poverty), 144 individuals were identified as having SLE per 100,000 in the population over a five-year period [54]. A diagnosis of glomerulonephritis was made in 21.5 percent of these patients (31 cases of lupus nephritis per 100,000 individuals in the population). The true prevalence of lupus nephritis in this high-risk population is likely to be higher since follow-up was only five years and since some patients may go undiagnosed.

The higher incidence of lupus nephritis among patients with SLE in the United States as compared with Europe may in part reflect racial and ethnic differences. The incidence of lupus nephritis is higher in blacks (34 to 51 percent), Hispanics (31 to 43 percent), and Asians (33 to 55 percent) than it is in whites (14 to 23 percent) [47,53,54]. Blacks and Hispanics also tend to present with more severe underlying histopathology, higher serum creatinine concentrations, and more proteinuria than whites [55]. In addition, blacks, Hispanics, and those living in poverty have a worse prognosis than whites and those with a higher socioeconomic status. However, the higher frequency of lupus nephritis in black populations persists even after correction for socioeconomic factors [54]. (See "Treatment and prognosis of diffuse or focal proliferative lupus nephritis", section on 'Race and ethnicity'.) Most renal abnormalities emerge soon after diagnosis (commonly, within the first 6 to 36 months) [1,47,56]. Although an elevated plasma creatinine concentration eventually develops in approximately 30 percent of all patients with SLE, evidence of decreased renal function is an uncommon manifestation within the first few years of diagnosis.

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&s…

5/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

The time course for the development of lupus nephritis varies with gender, age, and ethnicity. In a retrospective study in the United States, males, younger patients (eg, less than 33 years of age at diagnosis), and nonwhites were at enhanced risk of developing nephritis earlier in the course of the disease [47].

CLINICAL FEATURES AND DIAGNOSIS In patients with SLE, the presence of nephritis is suspected by an abnormal urinalysis and/or elevation of the serum creatinine, and the diagnosis is confirmed by histopathologic findings on renal biopsy. As noted above, some patients already have evidence of renal involvement at the time of SLE diagnosis. (See 'Epidemiology' above.) Detection of renal involvement — Patients with SLE should undergo testing for renal involvement at regular intervals, including a urinalysis with examination of the urinary sediment (looking for hematuria and cellular casts), an estimation of urine protein excretion (usually a spot urine protein-to-creatinine ratio), and a serum creatinine and estimated glomerular filtration rate. Elevated anti-DNA titers and low complement (C3 and C4) levels often indicate active lupus, particularly lupus nephritis, although the utility of serological assessment differs among patients. The frequency of testing depends upon whether or not the patient has a previous history of renal involvement. In patients who have never been diagnosed with renal disease, this evaluation is typically performed by a rheumatologist. These issues are discussed elsewhere. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Assessment of disease activity and severity'.) Diagnosis by kidney biopsy — A kidney biopsy should be performed in most patients with SLE who develop evidence of renal involvement in order to establish the diagnosis and, as discussed below, the class of lupus nephritis. Determining the class of lupus nephritis is important for the following reasons: ●

Treatment is guided by the histologic subtype (ie, the International Society of Nephrology [ISN]/Renal Pathology Society [RPS] class, the degree of activity and chronicity, and by complicating lesions such as interstitial nephritis and thrombotic microangiopathy).

●

The clinical presentation may not accurately reflect the severity of the histologic findings. As an example, infrequently, proliferative lupus may be present even if the patient has minimal proteinuria and a normal serum creatinine.

However, patients with proteinuria that is less than 500 mg/day and a bland urine sediment do not need to undergo a kidney biopsy. Such patients are unlikely to have a class of nephritis that warrants immunosuppressive therapy unless worsening kidney function is noted during follow-up examinations. These issues are presented in detail separately. (See "Indications for renal biopsy in patients with lupus nephritis".) https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&s…

6/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

The histopathology of lupus nephritis can be quite varied, and, at times, lupus nephritis may be confused with other immune complex-mediated glomerulonephritides. However, some histopathologic features are highly characteristic of lupus nephritis. These include: ●

Glomerular deposits that stain dominantly for IgG and contain co-deposits of immunoglobulin A (IgA), immunoglobulin M (IgM), C3, and C1q, the so-called "full house" immunofluorescence pattern. Less commonly, the full house immunofluorescence pattern may also be seen in patients with endocarditis [57], HIV [58], hepatitis C [59], a portosystemic shunt [60], and poststreptococcal glomerulonephritis.

●

Glomerular deposits simultaneously seen in the mesangial, subendothelial, and subepithelial locations.

●

Extraglomerular immune-type deposits within tubular basement membranes, the interstitium, and blood vessels.

●

Tubuloreticular inclusions in the glomerular endothelial cells (picture 1). These inclusions are composed of ribonucleoprotein and membrane, and their synthesis is stimulated by alphainterferon [61]. The only other circumstances in which these structures are prominent are in HIV nephropathy (associated with chronically high levels of circulating alpha-interferon) and treatment with alpha-interferon. However, patients with HIV nephropathy typically have collapsing focal segmental glomerulosclerosis rather than a proliferative glomerulonephritis with immune complex deposition. (See "HIV-associated nephropathy (HIVAN)".)

CLASSIFICATION Most patients with lupus nephritis have an immune complex-mediated glomerular disease. Over the last two decades, there have been several attempts by different societies to classify the different glomerulopathies associated with SLE. Based upon clinicopathologic correlations, a lupus nephritis classification system was developed by a group of renal pathologists, nephrologists, and rheumatologists in 2004 (the Renal Pathology Society/International Society of Nephrology, or RPS/ISN, classification) [62-64]. This system appears to provide increased reproducibility compared with the modified 1982 World Health Organization (WHO) system [64-67]. The ISN classification system divides glomerular disorders associated with SLE into six different patterns (or classes) based upon kidney biopsy histopathology [62,63]. Although the different classes tend to have distinct histologic, clinical, and prognostic characteristics, there is substantial overlap due in part to variations in sampling. Ideally, the biopsy specimen should contain at least 25 glomeruli. In addition, a significant percentage of patients evolve from one class of lupus nephritis to another, sometimes after therapy and sometimes spontaneously [62,68-72]. The https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&s…

7/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

evolution from one class of nephritis to another is not surprising, since the different histologic types represent nonspecific responses to immune complex deposition. Various serologic and urine markers have been examined as potential noninvasive determinants of histologic class [73], including the combination of an elevated anti-DNA titer and low complement levels, anti-C1q antibodies [74], tumor necrosis factor-like weak inducer of apoptosis (TWEAK) [75], and urinary neutrophil gelatinase-associated lipocalin (NGAL) [76]. However, no serum or urine marker of disease activity provides the degree of information that is gained by histopathology. Thus, classification of lupus nephritis is determined by kidney biopsy. Minimal mesangial lupus nephritis (class I) — This class of lupus nephritis is rarely, if ever, diagnosed because these patients typically have a normal urinalysis, no or minimal proteinuria, and a normal serum creatinine. As a result, a biopsy is not usually performed. Patients with class I disease have only mesangial immune deposits that are identified by immunofluorescence alone or by both immunofluorescence and electron microscopy, but such patients do not have light microscopic abnormalities. Minimal mesangial lupus nephritis (class I) represents the earliest and mildest form of glomerular involvement. (See "Indications for renal biopsy in patients with lupus nephritis".) Mesangial proliferative lupus nephritis (class II) — The histologic changes with class II disease are manifest clinically by microscopic hematuria and/or proteinuria. Hypertension is uncommon, and the nephrotic syndrome and renal insufficiency are virtually never seen. Light microscopy with class II disease reveals mesangial hypercellularity (of any degree) or mesangial matrix expansion (picture 2). A few isolated subepithelial or subendothelial deposits may be seen on immunofluorescence or electron microscopy. Visible subendothelial deposits on light microscopy or any global or segmental glomerular scars (which are thought to be the result of previous endocapillary proliferation, necrosis, or crescents) are inconsistent with the diagnosis of class II lupus nephritis. Such findings would indicate either class III or IV disease. Extensive podocyte effacement with nephrotic syndrome can rarely be seen, resembling minimal change disease if there is an associated podocytopathy. The renal prognosis with mesangial proliferative lupus nephritis is excellent, and no specific therapy is indicated unless the patient progresses to more advanced disease or has evidence of extensive podocyte effacement and nephrosis. (See 'Glomerular podocytopathy (lupus podocytopathy)' below.) Focal lupus nephritis (class III) — Patients with class III lupus nephritis usually have hematuria and proteinuria, and some patients will also have hypertension, a decreased glomerular filtration rate, and/or nephrotic syndrome. Class III disease is defined histologically by the following: ●

Less than 50 percent of glomeruli are affected by light microscopy. If more than 50 percent are involved, then the disease would be defined as diffuse lupus nephritis (class IV). Although less than 50 percent of glomeruli are affected on light microscopy, immunofluorescence microscopy (for IgG and C3) reveals almost uniform involvement [77].

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&s…

8/33

19/09/2019

●

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

Active or inactive endocapillary or extracapillary glomerulonephritis is almost always segmental (ie, involves less than 50 percent of the glomerular tuft) [63]. Electron microscopy usually reveals immune deposits in the subendothelial space of the glomerular capillary wall as well as the mesangium.

There are also subclasses of class III disease that are determined by the inflammatory activity (or chronicity) of the lesions [62,63]: ●

Class III (A), which is class III disease with active lesions. This is also called focal proliferative lupus nephritis.

●

Class III (A/C), which is associated with active and chronic lesions. This is referred to as focal proliferative and sclerosing lupus nephritis.

●

Class III (C), in which chronic inactive lesions with scarring are observed. This is also called focal sclerosing lupus nephritis.

Additional histologic features include the proportion of glomeruli affected by fibrinoid necrosis and crescents, and the presence or absence of tubulointerstitial or vascular abnormalities. Determining prognosis in class III disease may be clouded by the inability to accurately determine the percent of glomeruli involved. This latter feature is due to the potential for sampling error induced by the relatively small number of glomeruli that are obtained on a typical percutaneous renal biopsy. (See "Indications for and complications of renal biopsy".) Diffuse lupus nephritis (class IV) — Class IV lupus nephritis is the most common histologic pattern and most severe form of lupus nephritis [78]. Hematuria and proteinuria are present in virtually all patients with active class IV disease, and the nephrotic syndrome, hypertension, and reduced glomerular filtration rate are all frequently seen. Affected patients typically have significant hypocomplementemia (especially C3) and elevated anti-DNA levels, especially during active disease [79]. Class IV lupus nephritis is defined histologically by the following: ●

More than 50 percent of glomeruli are affected by light microscopy. If less than 50 percent are involved, then the disease would be defined as focal lupus nephritis (class III).

●

Affected glomeruli display endocapillary with or without extracapillary glomerulonephritis. These lesions may be either segmental (class IV-S, involving less than 50 percent of the glomerular tuft) or global (class IV-G, involving more than 50 percent of the glomerular tuft) (picture 3). Mesangial abnormalities may also be observed. Electron microscopy reveals subendothelial deposits, at least during the active phase (picture 1). The presence of diffuse wire loop deposits, but with little or no glomerular proliferation, is also considered class IV disease.

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&s…

9/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

There are also subclasses of class IV disease that are determined by whether affected glomeruli are involved segmentally (S) or globally (G), and by the inflammatory activity (or chronicity) of the lesions [62,63]: ●

Class IV-S (A), which is class IV-S with active lesions. This is also called diffuse segmental proliferative nephritis.

●

Class IV-G (A), which is class IV-G associated with active lesions. This is also referred to as diffuse global proliferative nephritis.

• A subset of patients with class IV-G (A) nephritis has severe segmental rather than true global glomerular lesions. However, because the segmental lesions in such patients involve more than 50 percent of affected glomerular tufts, they are classified as global (class IV-G) instead of segmental (class IV-S). Some investigators refer to this subgroup of lupus nephritis as class IV-Q disease [80].

• Compared with patients who have class IV-S and true global class IV-G disease, those with class IV-Q nephritis have a significantly lower remission rate and a significantly higher incidence of end-stage renal disease [80]. ●

Class IV-S (A/C), which is associated with active and chronic lesions. This is also called diffuse segmental proliferative and sclerosing nephritis.

●

Class IV-G (A/C), which is class IV-G with active and chronic lesions. This is also called diffuse global proliferative and sclerosing nephritis.

●

Class IV-S (C), which is associated with chronic inactive lesions with scars. This is also referred to as diffuse segmental sclerosing lupus nephritis.

●

Class IV-G (C), which is class IV-G with chronic inactive lesions with scars. This is also called diffuse global sclerosing lupus nephritis.

With active disease, proliferative and necrotizing lesions and crescent formation all may be present, affecting more than 50 percent of glomeruli on light microscopy [77,78]. The marked deposition of immunoglobulins (especially IgG) and complement (especially C3) in this setting (picture 4) results in thickening of the glomerular capillary wall (picture 1) and a pattern on light microscopy that is similar to that in membranoproliferative glomerulonephritis. These lesions are characterized by the marked influx of proinflammatory cells (monocytes, suppressor/cytotoxic T cells), sometimes resulting in cellular crescents [81,82]. Lupus membranous nephropathy (class V) — Patients with class V lupus nephritis typically present with signs of the nephrotic syndrome, similar to that in idiopathic membranous nephropathy [6,69,83]. Microscopic hematuria and hypertension may also be seen at presentation, and the creatinine concentration is usually normal or only slightly elevated. https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

10/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

Class V disease is characterized by diffuse thickening of the glomerular capillary wall on light microscopy (picture 5) and by subepithelial immune deposits (either global or segmental involvement) on immunofluorescence or electron microscopy (picture 6) [63,83,84]. Mesangial involvement may also be seen. Although sparse subendothelial deposits can be seen by immunofluorescence or electron microscopy with class V disease alone, the presence of such deposits as detected by light microscopy warrants a combined diagnosis of classes III and V disease, or of classes IV and V disease. In this setting, the additional designation of class III or IV is based upon the distribution of the deposits. Lupus membranous nephropathy may present with no other clinical or serologic manifestations of SLE (eg, complement levels may be normal, and anti-DNA antibodies may not be detectable). There are, however, several findings on electron and immunofluorescence microscopy that, if present, strongly suggest underlying lupus rather than idiopathic membranous nephropathy. These issues are discussed elsewhere. (See "Clinical features and therapy of lupus membranous nephropathy".) Advanced sclerosing lupus nephritis (class VI) — Patients with advanced sclerosing glomerulonephritis usually display slowly progressive renal dysfunction in association with proteinuria and a relatively bland urine sediment. Class VI disease is characterized by global sclerosis of more than 90 percent of glomeruli. It represents healing of prior inflammatory injury, as well as the advanced stage of chronic class III, IV, or V lupus nephritis. Active glomerulonephritis should not be observed. A retrospective study found that 4 percent of 169 renal biopsies from patients with lupus nephritis were classified with type VI disease [85]. Identification of this lesion via renal biopsy is important since immunosuppressive therapy is unlikely to be beneficial. Overlap of lupus and ANCA-associated glomerulonephritis — Antineutrophil cytoplasmic antibodies (ANCA) are detected by indirect immunofluorescence in approximately 20 percent of patients with SLE [86]. In addition, some patients with lupus nephritis have histologic features of a superimposed ANCA-associated glomerulonephritis, including prominent necrosis and crescent formation with minimal or absent endocapillary proliferation or subendothelial deposits [87-89]. The prevalence of crescentic glomerulonephritis with ANCA-associated glomerulonephritis was examined in a Chinese series of 327 patients with lupus nephritis [88]. The following observations were made: ●

Of the 327 patients, 152 had class IV-G nephritis (46 percent).

●

Of those with class IV-G nephritis, 33 had crescentic glomerulonephritis (22 percent of patients with class IV-G nephritis, and 10 percent of the total).

●

Of those with crescents, 10 had a positive ANCA (30 percent of patients with crescents, and 3 percent of the total), including nine with a p-ANCA (perinuclear ANCA). Positive ANCA

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

11/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

serologies were far less common in patients without crescents (2 percent). ●

It was unclear whether or not the histologic features and clinical outcomes of patients with crescentic glomerulonephritis differed according to ANCA status.

The treatment of patients with an apparent overlap of lupus and ANCA-associated glomerulonephritis is presented elsewhere. (See "Treatment and prognosis of diffuse or focal proliferative lupus nephritis", section on 'Initial (induction) therapy'.) Renal-limited lupus-like nephritis — Some patients with renal disease have a histologic pattern of injury that is indistinguishable from lupus nephritis, but have no extrarenal symptoms, signs, or serologies suggestive of SLE [90-92]. This pattern was described in four women who presented with hematuria, proteinuria, and variable degrees of renal dysfunction [90]. Renal biopsy in each patient revealed characteristic findings of lupus nephritis, including proliferative glomerulonephritis, a "full house" pattern of immune complex deposition as described above, and endothelial cell tubuloreticular inclusions. However, extrarenal signs of SLE were absent, antinuclear antibody (ANA) titers were negative or weakly positive, complement levels were normal, and anti-DNA titers were negative. Other causes of glomerulonephritis were also excluded. All four patients were treated with glucocorticoids with or without mycophenolate mofetil and cyclophosphamide, and, despite immunosuppression, three had progressive disease and required renal replacement therapy. Some patients, mostly children with lesions of class V nephritis, initially present with a "lupus-like" lesion and, after a variable period, develop clinical and/or serological features of SLE [91,93]. In those cases, the glomerulonephritis simply heralds the arrival of overt SLE.

OTHER RENAL DISEASES ASSOCIATED WITH LUPUS In addition to the glomerulopathies, there are other forms of lupus renal disease: tubulointerstitial nephritis; vascular disease; and renal disease infrequently associated with drug-induced lupus. The investigators responsible for the newest classification system of glomerular disease emphasize that the presence and severity of tubulointerstitial and vascular involvement should be noted in any biopsy specimen [62,63]. Tubulointerstitial nephritis — Tubulointerstitial disease (interstitial infiltrate, tubular injury) with or without immune deposits along the tubular basement membrane is a common finding in lupus nephritis and is almost always associated with concurrent glomerular disease [94,95]. The severity of the tubulointerstitial involvement is an important prognostic sign, correlating positively with the presence of hypertension, an elevated plasma creatinine concentration, and a progressive clinical course [95-97]. In a study of 313 patients from China with lupus nephritis, for example, the presence of tubulointerstitial nephritis was significantly associated with a twofold higher risk of developing end-stage renal disease or a doubling of serum creatinine after controlling for other https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

12/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

prognostic indicators [97]. As expected, both tubular atrophy and interstitial fibrosis were also associated with an increased risk. By contrast, the presence of tubular basement membrane deposits alone correlates with the serologic activity of the disease, but not the prognosis [95]. In a few cases, tubulointerstitial disease is the only manifestation of lupus nephritis. This possibility should be suspected when a patient with lupus presents with a rising plasma creatinine concentration and a urinalysis that is relatively normal or shows only a few red cells and/or white cells [98,99]. These changes may be accompanied by signs of tubular dysfunction such as metabolic acidosis due to type 1 (distal) renal tubular acidosis, hyperkalemia due to impaired distal potassium secretion, or hypokalemia due to salt wasting and secondary hyperaldosteronism [100,101]. Autoantibodies directed against the acid-secreting intercalated cells in the collecting tubule may be responsible for the acid secretory defect in at least some patients [102]. A review of the mechanisms by which distal acid secretion can be altered is discussed elsewhere. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance".) Vascular disease — Involvement of the renal vasculature is not uncommon in lupus nephritis, and its presence can adversely affect the prognosis of the renal disease [85,103,104]. The most frequent manifestations are immune complex deposition (which is typically associated with immune deposits in the glomeruli), immunoglobulin microvascular "thrombi," a thrombotic microangiopathy leading to a syndrome similar to thrombotic thrombocytopenic purpura (TTP), vasculitis, or atheroembolic disease and atherosclerosis [85,103,105-107]. Vascular immune deposits are usually located beneath an intact endothelium. They typically produce no inflammation; however, fibrinoid necrosis with vascular narrowing can be seen in severe cases, often in association with moderate to severe hypertension [104]. It is unclear in this setting whether the hypertension contributes to the vascular injury and/or whether the vascular narrowing exacerbates the hypertension via activation of the renin-angiotensin system. Regardless of the pathogenesis, patients with necrotizing vasculopathy tend to have a worse renal prognosis than those with isolated glomerular disease. Rarely, patients with lupus nephritis develop renal vein thrombosis [108]. These patients are typically nephrotic or have high antiphospholipid antibody levels, and the pathogenesis and treatment of the renal vein thrombosis are similar to that in patients without lupus. (See "Hypercoagulability in nephrotic syndrome".) Thrombotic microangiopathy — Other patients present with glomerular and vascular thrombi, often in association with antiphospholipid antibodies such as the lupus anticoagulant (LA) and anticardiolipin antibodies, or antibodies against the von Willebrand factor convertase (ADAMTS13). The name "LA" refers to the ability of these antibodies to produce in vitro prolongation of the partial thromboplastin time. In vivo, however, antiphospholipid antibodies promote coagulation, leading to venous and arterial thromboses, thrombocytopenia, livedo

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

13/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

reticularis, and, in women, frequent miscarriages. (See "Antiphospholipid syndrome and the kidney".) Silent lupus nephritis — Studies in which renal biopsy is performed in patients without any clinical evidence of renal disease have found mesangial, focal, or diffuse proliferative glomerulonephritis in some patients [109-114]. In one study, for example, kidney biopsy was offered to all patients with SLE seen at a Japanese hospital over an 11-year period, whether or not clinical signs of renal disease were present [114]. Of the 195 patients who had adequate biopsies, 86 had no clinical renal involvement. Of these 86 patients without clinical renal disease, 13 (15 percent) had either class III or IV lupus nephritis, and 9 (10 percent) had class V (membranous) disease. The renal disease in patients with silent lupus nephritis often remains clinically silent and is associated with a benign renal outcome [110,111,114]. This situation was illustrated in a series of 18 patients with silent lupus nephritis (one-half of whom were treated with glucocorticoids with or without cyclophosphamide) seen at a single center [111]. At a mean postbiopsy follow-up of 13 years, the mean serum creatinine was 0.8 mg/dL (71 micromol/L), the mean creatinine clearance was 108 mL/min, and all had a normal urinalysis. However, 15 of these patients had only mesangial disease at initial biopsy. Drug-induced lupus — A variety of drugs can induce a lupus-like syndrome, such as minocycline, hydralazine, isoniazid and, historically, procainamide. Renal involvement is uncommon, but a proliferative glomerulonephritis or the nephrotic syndrome can occur. (See "Drug-induced lupus".) Glomerular podocytopathy (lupus podocytopathy) — Some investigators have demonstrated that a glomerular podocytopathy due to renal involvement in lupus can be associated with diffuse epithelial cell foot process effacement without immune complex deposition, which is the classic histologic finding of minimal change disease [115-117]. Such lesions have been termed "lupus podocytopathy" [118]. In a retrospective study of 470 renal biopsies from patients with SLE, biopsies with normal light microscopy or a histologic diagnosis of either focal segmental glomerulosclerosis or mesangial proliferative glomerulonephritis were further evaluated [115]. The absence of endocapillary proliferation or necrosis, or of electron-dense glomerular basement membranes (GBM) deposits, was found in 18 such biopsies, of which eight were from patients with nephrotic-range proteinuria. At least 80 percent foot process effacement was observed in all but one of these eight patients. There is a possibility that these observations reflect the chance occurrence of SLE and either minimal change nephropathy and/or focal segmental glomerulosclerosis. However, this should occur in less than 1 in 10,000 cases, a frequency that is much less than that observed in this study (7 of 470). In addition, the onset of podocytopathy in these patients is seen most commonly at the onset of SLE or in the setting of a disease flare. https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

14/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

The presence of severe foot process effacement in the absence of deposits in the glomerular capillary wall implies a mechanism that is independent of immune complex deposition, presumably similar to the mechanism of primary minimal change disease or primary focal segmental glomerulosclerosis. Proposed explanations include production of a cytokine or lymphokine toxic to podocytes, or podocyte injury driven by T cell dysfunction. A number of lupus podocytopathy cases have been linked to nonsteroidal anti-inflammatory drug use for SLE [115,117,118]. Patients with a lupus-related podocytopathy often respond to a short course of high-dose glucocorticoids, similar to patients with isolated minimal change disease [119]. (See "Treatment of minimal change disease in adults".) Collapsing glomerulosclerosis — Collapsing glomerulosclerosis is histologically characterized by the collapse of the glomerular capillary tuft with epithelial cell proliferation in the Bowman's space and is clinically characterized by the nephrotic syndrome, renal impairment, and rapid progression to end-stage renal disease. Collapsing glomerulosclerosis is most often due to HIV. (See "HIV-associated nephropathy (HIVAN)".) However, collapsing glomerulosclerosis can also be seen in patients with lupus, usually during an active lupus flare [120]. In addition, such patients may have concurrent lupus nephritis. These issues are described in detail elsewhere. (See "Collapsing focal segmental glomerulosclerosis not associated with HIV infection".)

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults" and "Society guideline links: Systemic lupus erythematosus".)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-toread materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

15/33

19/09/2019

●

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

Basics topic (see "Patient education: Lupus and kidney disease (The Basics)")

SUMMARY ●

An abnormal urinalysis (hematuria and/or proteinuria) with or without an elevated plasma creatinine concentration is observed in the majority of patients with systemic lupus erythematosus (SLE). The most frequently observed abnormality is proteinuria. (See 'Introduction' above.)

●

A widely used classification system of lupus nephritis divides the glomerular disorders into six different patterns or classes based upon kidney biopsy findings. (See 'Classification' above.)

●

Class I disease (minimal mesangial lupus nephritis) is characterized by mesangial immune deposits that are identified either by immunofluorescence alone or by immunofluorescence and electron microscopy, but without light microscopic abnormalities. Patients with class I disease generally have a normal urinalysis and serum creatinine concentration. (See 'Minimal mesangial lupus nephritis (class I)' above.)

●

Class II disease (mesangial proliferative lupus nephritis) is characterized by mesangial hypercellularity or mesangial matrix expansion on light microscopy. A few isolated subepithelial or subendothelial deposits may be seen on immunofluorescence or electron microscopy, but no subendothelial deposits are visible on light microscopy. Patients present with microscopic hematuria and/or proteinuria; hypertension is uncommon, and the nephrotic syndrome and renal insufficiency are virtually never seen. (See 'Mesangial proliferative lupus nephritis (class II)' above.)

●

Class III disease (focal lupus nephritis) is defined by light microscopic appearance of endocapillary or extracapillary glomerulonephritis that involves fewer than 50 percent of glomeruli. Lesions are associated with focal subendothelial deposits on electron microscopy. Class III disease is further categorized depending upon the chronicity of the lesions. Hematuria and proteinuria are seen in almost all patients, some of whom also have the nephrotic syndrome, hypertension, and/or an elevated plasma creatinine concentration. Progressive renal dysfunction is uncommon when fewer than 25 percent of glomeruli are affected and when glomeruli show only segmental areas of proliferation without necrosis. (See 'Focal lupus nephritis (class III)' above.)

●

Class IV (diffuse lupus nephritis) is defined by more than 50 percent of glomeruli displaying endocapillary with or without extracapillary glomerulonephritis. Class IV disease is further categorized into segmental (IV-S) and global (IV-G) depending upon whether affected glomeruli have segmental or global lesions, respectively. Additional subclasses of class IV disease are categorized depending upon the chronicity of the lesions. Hematuria and proteinuria are present in all patients with active disease, and nephrotic syndrome,

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

16/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

hypertension, and renal insufficiency are frequently observed. (See 'Diffuse lupus nephritis (class IV)' above.) ●

Class V (lupus membranous nephropathy) is characterized by diffuse thickening of the glomerular capillary wall on light microscopy and by subepithelial immune deposits on immunofluorescence or electron microscopy. Although subendothelial deposits can be seen by immunofluorescence or electron microscopy alone, the presence of such deposits as detected by light microscopy warrants a combined diagnosis of class III or IV and V diseases. Patients primarily present with nephrotic syndrome, although hematuria and hypertension may be seen. At presentation, the plasma creatinine concentration is usually normal or only slightly elevated. (See 'Lupus membranous nephropathy (class V)' above.)

●

Class VI disease (advanced sclerosing lupus nephritis) is characterized by global sclerosis involving more than 90 percent of glomeruli. It represents healing of prior inflammatory injury, as well as the advanced stage of chronic class III, IV, or V lupus nephritis. Patients display slowly progressive renal dysfunction in association with proteinuria and a relatively bland urine sediment. (See 'Advanced sclerosing lupus nephritis (class VI)' above.)

●

Some patients with lupus nephritis have histologic features of a superimposed antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, including prominent necrosis and crescent formation with minimal or absent endocapillary proliferation or subendothelial deposits. (See 'Overlap of lupus and ANCA-associated glomerulonephritis' above.)

●

Tubulointerstitial disease often occurs with concurrent glomerular disease and is occasionally the only manifestation of lupus nephritis. Patients present with a rising plasma creatinine concentration and a relatively bland urinalysis. Signs of tubular dysfunction may be present. (See 'Tubulointerstitial nephritis' above.)

●

Vascular disease (such as thrombotic microangiopathy) is common and can adversely affect the prognosis of the renal disease. Patients may present with glomerular and vascular thrombi, often in association with antiphospholipid antibodies such as the lupus anticoagulant (LA) and anticardiolipin antibodies. (See 'Vascular disease' above.)

●

Silent lupus nephritis is defined as the presence of mesangial, focal, or diffuse proliferative glomerulonephritis in patients without clinical evidence of renal disease. Silent lupus nephritis is both rare and usually associated with a benign renal outcome. (See 'Silent lupus nephritis' above.)

●

A variety of drugs can induce a lupus-like syndrome, but renal involvement is usually uncommon. (See 'Drug-induced lupus' above.)

●

A glomerular podocytopathy due to lupus (also known as "lupus podocytopathy") is characterized by nephrotic syndrome, a biopsy that reveals diffuse and severe foot process

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

17/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

effacement, and the absence of subendothelial or subepithelial immune deposits. (See 'Glomerular podocytopathy (lupus podocytopathy)' above.)

ACKNOWLEDGMENT The editorial staff at UpToDate would like to acknowledge Peter H Schur, MD, who contributed to an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES 1. Almaani S, Meara A, Rovin BH. Update on Lupus Nephritis. Clin J Am Soc Nephrol 2017; 12:825. 2. Parikh SV, Rovin BH. Current and Emerging Therapies for Lupus Nephritis. J Am Soc Nephrol 2016; 27:2929. 3. Ortega LM, Schultz DR, Lenz O, et al. Review: Lupus nephritis: pathologic features, epidemiology and a guide to therapeutic decisions. Lupus 2010; 19:557. 4. O'Flynn J, Flierman R, van der Pol P, et al. Nucleosomes and C1q bound to glomerular endothelial cells serve as targets for autoantibodies and determine complement activation. Mol Immunol 2011; 49:75. 5. Alarcón GS. Multiethnic lupus cohorts: what have they taught us? Reumatol Clin 2011; 7:3. 6. Kashgarian M. Lupus nephritis: lessons from the path lab. Kidney Int 1994; 45:928. 7. Fries JW, Mendrick DL, Rennke HG. Determinants of immune complex-mediated glomerulonephritis. Kidney Int 1988; 34:333. 8. Hulsey M, Goldstein R, Scully L, et al. Anti-ribosomal P antibodies in systemic lupus erythematosus: a case-control study correlating hepatic and renal disease. Clin Immunol Immunopathol 1995; 74:252. 9. Ben-Yehuda A, Rasooly L, Bar-Tana R, et al. The urine of SLE patients contains antibodies that bind to the laminin component of the extracellular matrix. J Autoimmun 1995; 8:279. 10. Akashi Y, Yoshizawa N. Participation of histones and ubiquitin in lupus nephritis. Nihon Jinzo Gakkai Shi 1995; 37:462. https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

18/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

11. Lefkowith JB, Gilkeson GS. Nephritogenic autoantibodies in lupus: current concepts and continuing controversies. Arthritis Rheum 1996; 39:894. 12. Mannik M, Merrill CE, Stamps LD, Wener MH. Multiple autoantibodies form the glomerular immune deposits in patients with systemic lupus erythematosus. J Rheumatol 2003; 30:1495. 13. Yin Y, Wu X, Shan G, Zhang X. Diagnostic value of serum anti-C1q antibodies in patients with lupus nephritis: a meta-analysis. Lupus 2012; 21:1088. 14. Krishnan MR, Wang C, Marion TN. Anti-DNA autoantibodies initiate experimental lupus nephritis by binding directly to the glomerular basement membrane in mice. Kidney Int 2012; 82:184. 15. Lech M, Anders HJ. The pathogenesis of lupus nephritis. J Am Soc Nephrol 2013; 24:1357. 16. Vlahakos DV, Foster MH, Adams S, et al. Anti-DNA antibodies form immune deposits at distinct glomerular and vascular sites. Kidney Int 1992; 41:1690. 17. D'Andrea DM, Coupaye-Gerard B, Kleyman TR, et al. Lupus autoantibodies interact directly with distinct glomerular and vascular cell surface antigens. Kidney Int 1996; 49:1214. 18. Kalaaji M, Fenton KA, Mortensen ES, et al. Glomerular apoptotic nucleosomes are central target structures for nephritogenic antibodies in human SLE nephritis. Kidney Int 2007; 71:664. 19. Budhai L, Oh K, Davidson A. An in vitro assay for detection of glomerular binding IgG autoantibodies in patients with systemic lupus erythematosus. J Clin Invest 1996; 98:1585. 20. Valle RR, Eaton RB, Schnneider G, Schur PH. Complement activation by antibodies to DNA in systemic lupus erythematosus measured by enzyme immunoassay. Clin Immunol Immunopathol 1985; 34:345. 21. Du H, Chen M, Zhang Y, et al. Cross-reaction of anti-DNA autoantibodies with membrane proteins of human glomerular mesangial cells in sera from patients with lupus nephritis. Clin Exp Immunol 2006; 145:21. 22. Yung S, Tsang RC, Leung JK, Chan TM. Increased mesangial cell hyaluronan expression in lupus nephritis is mediated by anti-DNA antibody-induced IL-1beta. Kidney Int 2006; 69:272. 23. Espeli M, Bökers S, Giannico G, et al. Local renal autoantibody production in lupus nephritis. J Am Soc Nephrol 2011; 22:296. 24. Seelen MA, Trouw LA, Daha MR. Diagnostic and prognostic significance of anti-C1q antibodies in systemic lupus erythematosus. Curr Opin Nephrol Hypertens 2003; 12:619. https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

19/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

25. Horváth L, Czirják L, Fekete B, et al. High levels of antibodies against Clq are associated with disease activity and nephritis but not with other organ manifestations in SLE patients. Clin Exp Rheumatol 2001; 19:667. 26. Marto N, Bertolaccini ML, Calabuig E, et al. Anti-C1q antibodies in nephritis: correlation between titres and renal disease activity and positive predictive value in systemic lupus erythematosus. Ann Rheum Dis 2005; 64:444. 27. Trouw LA, Groeneveld TW, Seelen MA, et al. Anti-C1q autoantibodies deposit in glomeruli but are only pathogenic in combination with glomerular C1q-containing immune complexes. J Clin Invest 2004; 114:679. 28. Schur PH. IgG subclasses--a review. Ann Allergy 1987; 58:89. 29. Schur PH, Monroe M, Rothfield N. The gammaG subclass of antinuclear and antinucleic acid antibodies. Arthritis Rheum 1972; 15:174. 30. Lewis EJ, Busch GJ, Schur PH. Gamma G globulin subgroup composition of the glomerular deposits in human renal diseases. J Clin Invest 1970; 49:1103. 31. Belmont HM, Abramson SB, Lie JT. Pathology and pathogenesis of vascular injury in systemic lupus erythematosus. Interactions of inflammatory cells and activated endothelium. Arthritis Rheum 1996; 39:9. 32. Malide D, Russo P, Bendayan M. Presence of tumor necrosis factor alpha and interleukin-6 in renal mesangial cells of lupus nephritis patients. Hum Pathol 1995; 26:558. 33. Bergijk EC, de Heer E, Hoedemaeker PJ, Bruijn JA. A reappraisal of immune-mediated glomerulosclerosis. Kidney Int 1996; 49:605. 34. Balomenos D, Rumold R, Theofilopoulos AN. Interferon-gamma is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice. J Clin Invest 1998; 101:364. 35. Vielhauer V, Anders HJ, Schlöndorff D. Chemokines and chemokine receptors as therapeutic targets in lupus nephritis. Semin Nephrol 2007; 27:81. 36. Delmas Y, Viallard JF, Solanilla A, et al. Activation of mesangial cells by platelets in systemic lupus erythematosus via a CD154-dependent induction of CD40. Kidney Int 2005; 68:2068. 37. Munroe ME, James JA. Genetics of Lupus Nephritis: Clinical Implications. Semin Nephrol 2015; 35:396. 38. Salmon JE, Millard S, Schachter LA, et al. Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans. J Clin Invest 1996; 97:1348. https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

20/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

39. Karassa FB, Trikalinos TA, Ioannidis JP, FcgammaRIIa-SLE Meta-Analysis Investigators. Role of the Fcgamma receptor IIa polymorphism in susceptibility to systemic lupus erythematosus and lupus nephritis: a meta-analysis. Arthritis Rheum 2002; 46:1563. 40. Karassa FB, Trikalinos TA, Ioannidis JP, Fc gamma RIIIA-SLE meta-analysis investigators. The Fc gamma RIIIA-F158 allele is a risk factor for the development of lupus nephritis: a meta-analysis. Kidney Int 2003; 63:1475. 41. Aitman TJ, Dong R, Vyse TJ, et al. Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 2006; 439:851. 42. Gelmetti AP, Freitas AC, Woronik V, et al. Polymorphism of the FcgammaRIIalpha IgG receptor in patients with lupus nephritis and glomerulopathy. J Rheumatol 2006; 33:523. 43. Morel L. Genetics of human lupus nephritis. Semin Nephrol 2007; 27:2. 44. Freedman BI, Langefeld CD, Andringa KK, et al. End-stage renal disease in African Americans with lupus nephritis is associated with APOL1. Arthritis Rheumatol 2014; 66:390. 45. Lin CP, Adrianto I, Lessard CJ, et al. Role of MYH9 and APOL1 in African and non-African populations with lupus nephritis. Genes Immun 2012; 13:232. 46. Cervera R, Khamashta MA, Font J, et al. Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. The European Working Party on Systemic Lupus Erythematosus. Medicine (Baltimore) 1993; 72:113. 47. Seligman VA, Lum RF, Olson JL, et al. Demographic differences in the development of lupus nephritis: a retrospective analysis. Am J Med 2002; 112:726. 48. Wang F, Wang CL, Tan CT, Manivasagar M. Systemic lupus erythematosus in Malaysia: a study of 539 patients and comparison of prevalence and disease expression in different racial and gender groups. Lupus 1997; 6:248. 49. Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore) 2003; 82:299. 50. Kasitanon N, Magder LS, Petri M. Predictors of survival in systemic lupus erythematosus. Medicine (Baltimore) 2006; 85:147. 51. To CH, Petri M. Is antibody clustering predictive of clinical subsets and damage in systemic lupus erythematosus? Arthritis Rheum 2005; 52:4003. 52. Alarcón GS, McGwin G Jr, Petri M, et al. Baseline characteristics of a multiethnic lupus cohort: PROFILE. Lupus 2002; 11:95. https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

21/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

53. Bastian HM, Roseman JM, McGwin G Jr, et al. Systemic lupus erythematosus in three ethnic groups. XII. Risk factors for lupus nephritis after diagnosis. Lupus 2002; 11:152. 54. Feldman CH, Hiraki LT, Liu J, et al. Epidemiology and sociodemographics of systemic lupus erythematosus and lupus nephritis among US adults with Medicaid coverage, 2000-2004. Arthritis Rheum 2013; 65:753. 55. Contreras G, Lenz O, Pardo V, et al. Outcomes in African Americans and Hispanics with lupus nephritis. Kidney Int 2006; 69:1846. 56. Nossent HC, Henzen-Logmans SC, Vroom TM, et al. Contribution of renal biopsy data in predicting outcome in lupus nephritis. Analysis of 116 patients. Arthritis Rheum 1990; 33:970. 57. Lee LC, Lam KK, Lee CT, et al. "Full house" proliferative glomerulonephritis: an unreported presentation of subacute infective endocarditis. J Nephrol 2007; 20:745. 58. Haas M, Kaul S, Eustace JA. HIV-associated immune complex glomerulonephritis with "lupus-like" features: a clinicopathologic study of 14 cases. Kidney Int 2005; 67:1381. 59. Ramos-Casals M, Font J, García-Carrasco M, et al. Hepatitis C virus infection mimicking systemic lupus erythematosus: study of hepatitis C virus infection in a series of 134 Spanish patients with systemic lupus erythematosus. Arthritis Rheum 2000; 43:2801. 60. Smet AD, Kuypers D, Evenepoel P, et al. 'Full house' positive immunohistochemical membranoproliferative glomerulonephritis in a patient with portosystemic shunt. Nephrol Dial Transplant 2001; 16:2258. 61. Rich SA. De novo synthesis and secretion of a 36-kD protein by cells that form lupus inclusions in response to alpha-interferon. J Clin Invest 1995; 95:219. 62. Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 2004; 65:521. 63. Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004; 15:241. 64. Furness PN, Taub N. Interobserver reproducibility and application of the ISN/RPS classification of lupus nephritis-a UK-wide study. Am J Surg Pathol 2006; 30:1030. 65. Yokoyama H, Wada T, Hara A, et al. The outcome and a new ISN/RPS 2003 classification of lupus nephritis in Japanese. Kidney Int 2004; 66:2382.

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

22/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

66. Markowitz GS, D'Agati VD. The ISN/RPS 2003 classification of lupus nephritis: an assessment at 3 years. Kidney Int 2007; 71:491. 67. Markowitz GS, D'Agati VD. Classification of lupus nephritis. Curr Opin Nephrol Hypertens 2009; 18:220. 68. Huong DL, Papo T, Beaufils H, et al. Renal involvement in systemic lupus erythematosus. A study of 180 patients from a single center. Medicine (Baltimore) 1999; 78:148. 69. Appel GB, Silva FG, Pirani CL, et al. Renal involvement in systemic lupud erythematosus (SLE): a study of 56 patients emphasizing histologic classification. Medicine (Baltimore) 1978; 57:371. 70. Lee HS, Mujais SK, Kasinath BS, et al. Course of renal pathology in patients with systemic lupus erythematosus. Am J Med 1984; 77:612. 71. Najafi CC, Korbet SM, Lewis EJ, et al. Significance of histologic patterns of glomerular injury upon long-term prognosis in severe lupus glomerulonephritis. Kidney Int 2001; 59:2156. 72. Lu J, Tam LS, Lai FM, et al. Repeat renal biopsy in lupus nephritis: a change in histological pattern is common. Am J Nephrol 2011; 34:220. 73. Rovin BH, Zhang X. Biomarkers for lupus nephritis: the quest continues. Clin J Am Soc Nephrol 2009; 4:1858. 74. Coremans IE, Spronk PE, Bootsma H, et al. Changes in antibodies to C1q predict renal relapses in systemic lupus erythematosus. Am J Kidney Dis 1995; 26:595. 75. Schwartz N, Rubinstein T, Burkly LC, et al. Urinary TWEAK as a biomarker of lupus nephritis: a multicenter cohort study. Arthritis Res Ther 2009; 11:R143. 76. Rubinstein T, Pitashny M, Levine B, et al. Urinary neutrophil gelatinase-associated lipocalin as a novel biomarker for disease activity in lupus nephritis. Rheumatology (Oxford) 2010; 49:960. 77. Schwartz MM, Kawala KS, Corwin HL, Lewis EJ. The prognosis of segmental glomerulonephritis in systemic lupus erythematosus. Kidney Int 1987; 32:274. 78. Schwartz MM, Lan SP, Bonsib SM, et al. Clinical outcome of three discrete histologic patterns of injury in severe lupus glomerulonephritis. Am J Kidney Dis 1989; 13:273. 79. Lloyd W, Schur PH. Immune complexes, complement, and anti-DNA in exacerbations of systemic lupus erythematosus (SLE). Medicine (Baltimore) 1981; 60:208.

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

23/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

80. Schwartz MM, Korbet SM, Lewis EJ, Collaborative Study Group. The prognosis and pathogenesis of severe lupus glomerulonephritis. Nephrol Dial Transplant 2008; 23:1298. 81. Akashi Y, Oshima S, Takeuchi A, et al. [Identification and analysis of immune cells infiltrating into the glomerulus and interstitium in lupus nephritis]. Nihon Rinsho Meneki Gakkai Kaishi 1995; 18:545. 82. Davis JC, Tassiulas IO, Boumpas DT. Lupus nephritis. Curr Opin Rheumatol 1996; 8:415. 83. Donadio JV Jr, Burgess JH, Holley KE. Membranous lupus nephropathy: a clinicopathologic study. Medicine (Baltimore) 1977; 56:527. 84. Jennette JC, Iskandar SS, Dalldorf FG. Pathologic differentiation between lupus and nonlupus membranous glomerulopathy. Kidney Int 1983; 24:377. 85. Descombes E, Droz D, Drouet L, et al. Renal vascular lesions in lupus nephritis. Medicine (Baltimore) 1997; 76:355. 86. Sen D, Isenberg DA. Antineutrophil cytoplasmic autoantibodies in systemic lupus erythematosus. Lupus 2003; 12:651. 87. Nasr SH, D'Agati VD, Park HR, et al. Necrotizing and crescentic lupus nephritis with antineutrophil cytoplasmic antibody seropositivity. Clin J Am Soc Nephrol 2008; 3:682. 88. Yu F, Tan Y, Liu G, et al. Clinicopathological characteristics and outcomes of patients with crescentic lupus nephritis. Kidney Int 2009; 76:307. 89. Hervier B, Hamidou M, Haroche J, et al. Systemic lupus erythematosus associated with ANCA-associated vasculitis: an overlapping syndrome? Rheumatol Int 2012; 32:3285. 90. Huerta A, Bomback AS, Liakopoulos V, et al. Renal-limited 'lupus-like' nephritis. Nephrol Dial Transplant 2012; 27:2337. 91. Gianviti A, Barsotti P, Barbera V, et al. Delayed onset of systemic lupus erythematosus in patients with "full-house" nephropathy. Pediatr Nephrol 1999; 13:683. 92. Jones E, Magil A. Nonsystemic mesangiopathic glomerulonephritis with "full house" immunofluorescence. Pathological and clinical observation in five patients. Am J Clin Pathol 1982; 78:29. 93. Shearn MA, Hopper J Jr, Biava CG. Membranous lupus nephropathy initially seen as idiopathic membranous nephropathy. Possible diagnostic value of tubular reticular structures. Arch Intern Med 1980; 140:1521.

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

24/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

94. Brentjens JR, Sepulveda M, Baliah T, et al. Interstitial immune complex nephritis in patients with systemic lupus erythematosus. Kidney Int 1975; 7:342. 95. Park MH, D'Agati V, Appel GB, Pirani CL. Tubulointerstitial disease in lupus nephritis: relationship to immune deposits, interstitial inflammation, glomerular changes, renal function, and prognosis. Nephron 1986; 44:309. 96. Alexopoulos E, Seron D, Hartley RB, Cameron JS. Lupus nephritis: correlation of interstitial cells with glomerular function. Kidney Int 1990; 37:100. 97. Yu F, Wu LH, Tan Y, et al. Tubulointerstitial lesions of patients with lupus nephritis classified by the 2003 International Society of Nephrology and Renal Pathology Society system. Kidney Int 2010; 77:820. 98. Tron F, Ganeval D, Droz D. Immunologically-mediated acute renal failure of nonglomerular origin in the course of systemic lupus erythematosus [SLE]. Report of two cases. Am J Med 1979; 67:529. 99. Singh AK, Ucci A, Madias NE. Predominant tubulointerstitial lupus nephritis. Am J Kidney Dis 1996; 27:273. 100. Kozeny GA, Barr W, Bansal VK, et al. Occurrence of renal tubular dysfunction in lupus nephritis. Arch Intern Med 1987; 147:891. 101. DeFronzo RA, Cooke CR, Goldberg M, et al. Impaired renal tubular potassium secretion in systemic lupus erythematosus. Ann Intern Med 1977; 86:268. 102. Bastani B, Underhill D, Chu N, et al. Preservation of intercalated cell H(+)-ATPase in two patients with lupus nephritis and hyperkalemic distal renal tubular acidosis. J Am Soc Nephrol 1997; 8:1109. 103. Wu LH, Yu F, Tan Y, et al. Inclusion of renal vascular lesions in the 2003 ISN/RPS system for classifying lupus nephritis improves renal outcome predictions. Kidney Int 2013; 83:715. 104. Appel GB, Pirani CL, D'Agati V. Renal vascular complications of systemic lupus erythematosus. J Am Soc Nephrol 1994; 4:1499. 105. Abdellatif AA, Waris S, Lakhani A, et al. True vasculitis in lupus nephritis. Clin Nephrol 2010; 74:106. 106. Kwok SK, Ju JH, Cho CS, et al. Thrombotic thrombocytopenic purpura in systemic lupus erythematosus: risk factors and clinical outcome: a single centre study. Lupus 2009; 18:16. 107. Song D, Wu LH, Wang FM, et al. The spectrum of renal thrombotic microangiopathy in lupus nephritis. Arthritis Res Ther 2013; 15:R12. https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

25/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

108. Gelfand J, Truong L, Stern L, et al. Thrombotic thrombocytopenic purpura syndrome in systemic lupus erythematosus: treatment with plasma infusion. Am J Kidney Dis 1985; 6:154. 109. Mahajan SK, Ordóñez NG, Feitelson PJ, et al. Lupus nephropathy without clinical renal involvement. Medicine (Baltimore) 1977; 56:493. 110. Leehey DJ, Katz AI, Azaran AH, et al. Silent diffuse lupus nephritis: long-term follow-up. Am J Kidney Dis 1982; 2:188. 111. Gonzalez-Crespo MR, Lopez-Fernandez JI, Usera G, et al. Outcome of silent lupus nephritis. Semin Arthritis Rheum 1996; 26:468. 112. Wada Y, Ito S, Ueno M, et al. Renal outcome and predictors of clinical renal involvement in patients with silent lupus nephritis. Nephron Clin Pract 2004; 98:c105. 113. Zabaleta-Lanz ME, Muñoz LE, Tapanes FJ, et al. Further description of early clinically silent lupus nephritis. Lupus 2006; 15:845. 114. Wakasugi D, Gono T, Kawaguchi Y, et al. Frequency of class III and IV nephritis in systemic lupus erythematosus without clinical renal involvement: an analysis of predictive measures. J Rheumatol 2012; 39:79. 115. Kraft SW, Schwartz MM, Korbet SM, Lewis EJ. Glomerular podocytopathy in patients with systemic lupus erythematosus. J Am Soc Nephrol 2005; 16:175. 116. Hu W, Chen Y, Wang S, et al. Clinical-Morphological Features and Outcomes of Lupus Podocytopathy. Clin J Am Soc Nephrol 2016; 11:585. 117. Dube GK, Markowitz GS, Radhakrishnan J, et al. Minimal change disease in systemic lupus erythematosus. Clin Nephrol 2002; 57:120. 118. Shea-Simonds P, Cairns TD, Roufosse C, et al. Lupus podocytopathy. Rheumatology (Oxford) 2009; 48:1616. 119. Bomback AS, Appel GB. Updates on the treatment of lupus nephritis. J Am Soc Nephrol 2010; 21:2028. 120. Salvatore SP, Barisoni LM, Herzenberg AM, et al. Collapsing glomerulopathy in 19 patients with systemic lupus erythematosus or lupus-like disease. Clin J Am Soc Nephrol 2012; 7:914.

Topic 3056 Version 28.0

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

26/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

GRAPHICS Subendothelial deposits and tubuloreticular inclusions in lupus nephritis

Electron micrograph in diffuse proliferative lupus nephritis shows massive subendothelial deposits (D) and characteristic tubuloreticular structures (arrow) in the endothelial cells (En). The subendothelial deposits cause marked thickening of the glomerular capillary wall, leading to a wire loop appearance on light microscopy. Ep: epithelial cell; GBM: glomerular basement membrane. Courtesy of Helmut Rennke, MD. Graphic 79072 Version 4.0

Electron micrograph of a normal glomerulus

Electron micrograph of a normal glomerular capillary loop showing the fenestrated endothelial cell (Endo), the glomerular basement membrane (GBM), and the epithelial cells with its interdigitating foot processes (arrow). The GBM is thin, and no electron-dense deposits are present. Two normal platelets are seen in the capillary lumen. Courtesy of Helmut G Rennke, MD. Graphic 50018 Version 7.0

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

27/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

Light micrograph showing mesangial proliferative glomerulonephritis

Light micrograph of a mesangial glomerulonephritis showing segmental areas of increased mesangial matrix and cellularity (arrows). This finding alone can be seen in many diseases, including lupus nephritis and IgA nephropathy. IgA: immunoglobulin A. Courtesy of Helmut G Rennke, MD. Graphic 80250 Version 5.0

Normal glomerulus

Light micrograph of a normal glomerulus. There are only 1 or 2 cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow), and the mesangial cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows). Courtesy of Helmut G Rennke, MD. Graphic 75094 Version 4.0

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

28/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

Light micrograph showing proliferative lupus nephritis

Light micrograph showing a proliferative pattern in lupus nephritis, characterized by areas of cellular proliferation (arrows) and by thickening of the glomerular capillary wall (due to immune deposits) that may be prominent enough to form a "wire loop" (arrowheads). Although proliferative changes can be focal (affecting less than 50 percent of glomeruli), disease of this severity is usually diffuse. Courtesy of Helmut G Rennke, MD. Graphic 60218 Version 7.0

Normal glomerulus

Light micrograph of a normal glomerulus. There are only 1 or 2 cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow), and the mesangial cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows). Courtesy of Helmut G Rennke, MD. Graphic 75094 Version 4.0

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

29/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

Immunofluorescence microscopy showing massive IgG deposition

Kidney biopsy from a patient with diffuse proliferative lupus nephritis showing, on immunofluorescence microscopy, massive, lumpy deposits of IgG. IgG: immunoglobulin G. Courtesy of Peter H Schur, MD. Graphic 70781 Version 7.0

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

30/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

Light micrograph showing lupus membranous nephropathy

Light micrograph of lupus membranous nephropathy. The changes are similar to those in any form of membranous nephropathy with diffuse thickening of the glomerular capillary wall being the major abnormality (short arrows). Focal areas of mesangial expansion and hypercellularity (long arrows) are the only findings suggestive of an underlying disease such as lupus, although they can also be seen in idiopathic membranous nephropathy. Courtesy of Helmut G Rennke, MD. Graphic 56549 Version 5.0

Normal glomerulus

Light micrograph of a normal glomerulus. There are only 1 or 2 cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow), and the mesangial cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows). Courtesy of Helmut G Rennke, MD. Graphic 75094 Version 4.0

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

31/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

Electron micrograph showing lupus membranous nephropathy

Electron micrograph of lupus membranous nephropathy. The subepithelial immune deposits (D) are characteristic of any form of membranous nephropathy, but the intraendothelial tubuloreticular inclusions (arrow) strongly suggest underlying lupus. GBM: glomerular basement membrane; Ep: epithelial cell. Courtesy of Helmut G Rennke, MD. Graphic 69348 Version 7.0

Electron micrograph of a normal glomerulus

Electron micrograph of a normal glomerular capillary loop showing the fenestrated endothelial cell (Endo), the glomerular basement membrane (GBM), and the epithelial cells with its interdigitating foot processes (arrow). The GBM is thin, and no electron-dense deposits are present. Two normal platelets are seen in the capillary lumen. Courtesy of Helmut G Rennke, MD. Graphic 50018 Version 7.0

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

32/33

19/09/2019

Diagnosis and classification of renal disease in systemic lupus erythematosus - UpToDate

Contributor Disclosures Andrew S Bomback, MD, MPH Nothing to disclose Gerald B Appel, MD Grant/Research/Clinical Trial Support: Sanofi Pharma [Alport syndrome (RG-012, for injection)]; Bristol-Myers Squibb [Focal Segmental Glomerulosclerosis (Abatacept)]; Achillion [C3 Glomerulopathies (ACH-0144471, tablets)]; EMD Serono [Immunoglobulin A nephropathy (Atacicept)]; Reata [Alport syndrome; variant-focal segmental glomerulosclerosis (Bardoxolone)]; Mallinkrodt [Focal Segmental Glomerulosclerosis (Corticotropin)]; Chemocentryx [C3 Glomerulopathies (Avacopan)]; Chemocentryx [Anti-Neutrophil Cytoplasmic Antibody Vasculitis (Avacopan)]. Speaker's Bureau: Genentech [Vasculitis (Rituximab)]; Sanofi [Side effects (Alemtuzumab)]. Consultant/Advisory Boards: Genentech; Bristol-Myers Squibb; Mallinckrodt Pharmaceuticals; EMD Serono; Merck; Pfizer; Genzyme-Sanofi; Omeros; Achillion Pharmaceuticals; Alnylam Pharmaceuticals; Reata; Chemocentryx [Immunosuppressives (Drugs under development for immunosuppression)]. Richard J Glassock, MD, MACP Speaker's Bureau: Genentech [Vasculitis (Rituximab)]. Consultant/Advisory Boards: Bristol-Myers Squibb [Lupus Nephritis, Focal Segmental Glomerulosclerosis (Abatacept)]; ChemoCentryx [Vasculitis, C3 Glomerulopathy, Focal Segmental Glomerulosclerosis (CCX-168, CCX-140)]; Retrophin [Focal Segmental Glomerulosclerosis (Sparsentan)]; Omeros [IgA Nephropathy]; Ionis [C3 Glomerulopathy]; Apellis [Complement Inhibition on Glomerular Disease]; Achillion [Complement inhibition]. Employment: American Society of Nephrology [Nephrology SelfAssessment Program]; Karger Publishers [American Journal of Nephrology]. Equity Ownership/Stock Options: Reata [Alport Syndrome, Pulmonary Hypertension, Diabetic Nephropathy (Bardoxolone)]. David S Pisetsky, MD, PhD Consultant/Advisory Boards: Celgene [Lupus (Phase 2 study of cereblon-modulating agent)]; Lilly [Rheumatoid arthritis (Baricitinib)]; DILIsym [Drug-induced liver injury]; EMD Serono [SLE (Evobrutinib)]. Albert Q Lam, MD Nothing to disclose Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy

https://www.uptodate.com/contents/diagnosis-and-classification-of-renal-disease-in-systemic-lupus-erythematosus/print?search=nefrite lupica&…

33/33